Прогресс в развитии лекарственных средств на основе пептида: платформы для доставки, терапевтические средства и вакцины.

Introduction

Since the introduction of insulin in 1922, peptide drugs have become a promising modality in human therapeutics. 1 Peptides offer the potency of biologics yet retain drug-like properties for oral availability and tissue penetration. Their superior specificity in targeting interactions, tunable half-lives, and typically lower toxicity and immunogenicity give peptides advantages over other modalities. 2 , 3 Manufacturing peptides also costs less than protein therapeutics. 4 With precise rational design and advances enabling improved bioavailability, peptide drugs are poised to overcome limitations of traditional small molecules and biologics. 3

Historically, early peptide drugs were primarily sourced from specific animals, including reptiles, amphibians, arachnids, gastropods, and venomous mammals. 5 However, the rarity of these animals and the challenges associated with extracting complex compounds from them hindered peptide drug development for several decades. 6 – 9 It wasn’t until the 1950s, with the emergence of peptide synthesis technologies, that peptides experienced accelerated advancement. Pioneering breakthroughs, such as Vincent Du Vigneaud’s synthesis of oxytocin and vasopressin 10 – 12 and Robert Merrifield’s solid-phase peptide synthesis, 13 paved the way for large-scale peptide production and the approvals of pioneering peptide drugs like goserelin for cancer in 1989 14 and enfuvirtide for HIV in 2003.

Today, with nearly 100 approved peptide drugs worldwide and ongoing transitions from preclinical to clinical trials, the peptide therapeutics market continues to grow. 15 Significant advancements include the approval of semaglutide (Rybelsus ® , Novo Nordisk A/S) as the first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) for managing type 2 diabetes mellitus (T2DM) and weight loss. 16 , 17 Sales data from 2024 highlights the market dominance of semaglutide formulations, with semaglutide injections (Ozempic ® ) led peptide drug sales, totaling $138.90 hundred million USD. Other semaglutide formulations followed suit, with injectable Trulicity ® at $71.30 hundred million USD and oral Rybelsus® at $27.20 hundred million USD (Fig. 8a ), reflecting the growing demand for peptide therapeutics.

Nowadays, research efforts in peptide development continue to advance rapidly. In November 2023, Eli Lilly introduced tirzepatide (Mounjaro ® /Zepbound ® ), the pioneering dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA for weight management and glycemic control. It demonstrated superior performance in the SURPASS phase III trials over single receptor agonists like dulaglutide and semaglutide. 18 Moreover, promising candidates are emerging, such as retaglutide for treating T2DM, fatty liver disease, and obesity by targeting the glucagon receptor (GCGR), gastric inhibitory polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). 19 Additionally, diagnostic applications like the first peptide radiopharmaceutical [ 68 Ga]Ga-DOTA-TOC for diagnosing somatostatin receptor-positive neuroendocrine tumors (NETs) underscore the versatility of peptide-based technologies. 20 To provide a clear presentation of the boom in peptide drug research, we have updated the data on marketed peptides and clinical trials from Wang et al.’s recent study 2 (Table 3 ).

Despite the advancements, challenges remain, particularly concerning the rapid clearance and degradation of peptide drugs, necessitating subcutaneous injection and increasing patient discomfort. However, ongoing developments in structural modifications and delivery systems hold promise for enabling oral peptide formulations with enhanced stability, bioavailability, and patient compliance. 21 Notably, cell-targeting peptide (CTP)-based platforms and peptide-drug conjugates (PDCs) show particular promise in overcoming challenges associated with traditional small molecule therapies, enhancing efficiency, and reducing adverse effects, 22 – 27 with multiple platforms now in clinical trials (Tables 5 and 6 ).

Furthermore, peptide innovation extends to the vaccine field, where peptide-based subunits offer heightened specificity, safety, and quality control compared to traditional whole-pathogen vaccines, 28 transitioning vaccine development from the empirical whole-pathogen era to the defined subunit era. This transition has enabled the proliferation of preclinical trials for peptide vaccines. During the singular year span of 2023–2024, over 200 clinical trials involving peptide vaccines for infectious diseases and cancer prevention and treatment were documented on ClinicalTrials.gov. Here, we provide updated phase III trial data up to 2024 (Table 7 ).

This review aims to provide a comprehensive analysis of the current status of peptide-based drug development (Fig. 1 ), emphasizing recent therapeutic advances, delivery systems, and vaccine innovations. Additionally, we discuss future advancements and obstacles in peptide therapeutics, highlighting the ongoing evolution of this promising field. Fig. 1 Visualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figure

Advance of peptide-based drug and development trend

Characteristics of peptide-based drugs

Peptides as therapeutic agents trace back to 1922, when Dr. Frederick Banting and colleagues first extracted insulin from animals and applied it in the treatment of type I diabetes. 29 Since then, peptides as therapeutic agents have played a pivotal role in human physiology, serving as hormones, neurotransmitters, growth factors, antimicrobials, and vaccines, among other functions. 30 – 34

Peptides represent a discrete family of pharmacological substances that lie between tiny molecules and proteins in molecular weight, yet display distinctive biological and physicochemical characteristics (Fig. 2 ). Therapeutic peptides are a kind of amino acid sequences that combine properties from large proteins or other biologics with small molecule medications. 3 , 35 Typically, these sequences have fewer than 50 residues in their chain. Peptides have advantages over proteins and antibodies, including lesser immunogenicity and lower cost of manufacture. The attachment of peptides to specific receptors elicits subsequent physiological responses, similar to the mechanism of action observed in protein and antibody medications. Peptides, on the other hand, can penetrate tissues more deeply because of their smaller size. Furthermore, peptides typically have fewer side effects because they are less immunogenic than therapeutic proteins and antibodies. 36 , 37 Chemical synthesis is widely regarded as the 、the most advanced technology for the production of therapeutic peptides particularly following the advent of solid-phase peptide synthesis (SPPS). 38 The primary advantages of SPPS are the facilitation of efficient separation of peptide products from impurities and byproducts. 39 Synthetic therapeutic peptides are a great option due to their lower cost and higher quality control compared to peptides or proteins obtained through enzymatic processes or recombinant technology. Furthermore, therapeutic peptides usually have a length of 10–50 amino acids, whereas antibodies have a binding site of 75 kDa. 40 – 42 This means that peptides have higher specific activity per unit mass (15–60 times higher), which lowers the cost per unit of active medicine. Peptides are also less expensive commercially since they are more stable and may be kept at room temperature. 43 Fig. 2 Advantages and limitations of peptide-based drugs. Peptides, small molecules, and biologics represent three distinct categories of therapeutic agents. Peptides possess certain advantages when compared to the other two classes. However, small molecules exhibit specific disadvantages relative to peptides, and biologics also present their own set of limitations. Figure 2 was created with biorender.com

Therapeutic peptides offer several advantages compared to traditional small molecule pharmaceuticals. First of all, peptides typically represent the smallest functional components of proteins, thereby exhibiting heightened selectivity and specificity compared to small molecule drugs, consequently reducing the likelihood of off-target adverse reactions. 44 Second, the degradation products of peptides in the body are amino acids, thereby diminishing the likelihood of systemic toxicity. 45 Thirdly, peptides seldom ever accumulate in tissues because of their brief half-life. 46 Due to its limited range (300–1000 A^2), small molecule drugs are difficult to effectively inhibit major biomolecular surface contacts, including protein-protein interactions (PPIs, contact area 1500–3000 A^2). Consequently, small molecule drugs encounter the challenge of effectively engaging key contact regions, thereby resulting in unintended off-target effects. 47 , 48 Peptides possessing greater molecular dimensions and increased conformational flexibility relative to small molecule drugs may offer a solution to the challenge. Monoclonal antibodies are also a class of PPI inhibitors. Peptides exhibit greater cellular uptake and affinity for intracellular receptors compared to monoclonal antibodies, thereby enhancing their potential for biological activity. Our group conducted a review of peptide drug studies focused on targeting PPIs, including MDM2/p53, Keap1/Nrf2, and PD-1/PD-L1. 49

Because of their instability in vivo and inadequate capacity to cross cell membranes, peptides present difficulties when being used in clinical settings. The main reason for this is that peptides have a lot of amino and carboxyl groups, which are difficult for them to pass lipid-based membrane structures since they frequently exhibit hydrophilicity, strong hydrogen bonding capacity, and low lipophilicity. 50 , 51 In addition, due to their limited stability in the body, peptides are rapidly degraded by digestive enzymes in the gastrointestinal tract. As a result, they are removed from circulation within minutes. Large-scale protein hydrolysis and/or quick clearance in the liver, kidneys, or blood are the primary causes of this phenomena. It is worth noting that, with few exceptions (such as cyclosporine A), the bioavailability of most peptides following oral administration is less than 1%. 52 This is primarily due to enzymatic degradation and pH-mediated hydrolysis in the gastrointestinal tract and liver, leading to low absorption rates and high first-pass effect. 53 Consequently, commercially available peptides are primarily delivered subcutaneously, limiting the feasibility of more compliant oral delivery. 54

The successful translation of peptide therapeutic candidates is dependent on high bioavailability and biodistribution, which include absorption and transport across biological membranes and cellular barriers. 55 Solubility, lipophilicity, hydrogen bonding, chemical stability, and metabolic stability are all factors that influence these traits. Thus, peptide optimization is required, and chemical optimization procedures for therapeutic peptides are based on studies of structure-activity relationships (SAR) and/or quantitative structure-activity relationships (QSAR) of newly synthesized peptides. The goal is to boost bioavailability, minimize elimination and biodegradation, and improve selectivity or affinity for receptors or targets. Furthermore, technological improvements stimulate the creation of new delivery systems, which provide effective peptide translation.

Bibliometric and visual analysis (2005–2024)

Here, we present an analysis based on a systematic and comprehensive literature search conducted on the PubMed database (Fig. 3 ). We used a series of key terms to formulate our search strategy, including “peptide”, “therapeutics”, “delivery systems”, “peptide vaccines”, and “drugs”, combined using the Boolean operators AND and OR. To refine our study, we utilized Medical Subject Headings (MeSH) terms and Boolean operators. Specifically, we searched for articles containing the term “peptide” either as a MeSH term or in the title/abstract, and also containing the terms “therapeutics”, “delivery”, “drug”, or “peptide vaccine”. We limited our search to articles published between 2005 and 2024. To further identify relevant articles, we analyzed the references of the selected papers and applied search filters to display publications within the specified timeframe only. Fig. 3 Analyses of literature on peptide drug published from 2005 to 2024. a Statistics of articles published by countries on drugs related to peptides. Among them, the United States had the highest number of publications, followed by China. b Statistics of the number of articles on peptide drugs for different diseases in the past 20 years. Over time, cancer has received increasing attention in peptide drugs. c New delivery methods for peptide drugs and visualization of the relationship between disease. As one of the most studied delivery methods, liposomes play an important role in the application of cardiovascular diseases. d Statistics of articles related to peptide drugs in the past 20 years. Among them, peptide vaccines have been widely valued by researchers

The final dataset comprised 87611 articles spanning 28 countries/regions. From these data, it’s evident that there is a sustained growth trend in the number of research articles focusing on peptides. The observed continued increase in the number of peptide-based articles reflects the increasing interest and research investment in peptides, particularly in 2019, when the number of articles published peaked, possibly owing to the milestone timing of the introduction of oral semaglutide. 56 Over the period from 2005 to 2024, the United States contributed the highest number of publications, followed by China (Fig. 3a ).

Key subject headings play a crucial role in summarizing the main ideas and core content of the literature. 57 By visualizing the co-occurrence of key words, researchers can obtain a concise overview of research trends and potential future directions, thus providing valuable insights. Among the keywords identified between 2005 and 2024, the most common one is “drug delivery system”, followed by “insulin” and “natriuretic peptide”. Firstly, in order to overcome the characteristics of peptide drugs that are easily hydrolyzed by digestive enzymes in the human gastrointestinal tract, 58 the development and update of peptide drug delivery systems have been a research hotspot for such drugs. Secondly, as two classic peptides with proven uses, insulin and natriuretic peptides are of great significance and have broad innovation prospects for the treatment of diabetes and cardiovascular diseases. Therefore, the development of peptide drug delivery methods focused on diabetes and cardiovascular diseases can visually represent the development of peptide drugs in the past 20 years.

In 2019, marketing approval was granted for oral semaglutide, the world’s first glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for the treatment of type 2 diabetes, providing a promising new treatment option for people with diabetes. This milestone event undoubtedly brings hope to diabetes patients. In addition to their success in the field of diabetes treatment, peptides have also shown potential in cancer treatment. Based on the search results from 2020 to 2024, the frequency of the keyword ‘cancer’ has surpassed that of type 2 diabetes mellitus (T2DM) as the most relevant disease in this field (Fig. 3b ). Therefore, peptides have been widely explored and applied in cancer therapy. On the one hand, peptides can directly kill tumour cells; on the other hand, as tumour-targeting peptides or peptide vaccines, they can enhance the therapeutic effect.

Based on the results of a search for peptide-based drug delivery systems, it is clear that oral, subcutaneous and intravenous administration have been the most commonly used modes of drug delivery over the past two decades. From the point of view of drug dosage form improvement, liposomes are the most popular, followed by hydrogels, polyethylene glycol and microgels. All these indicate that with the advancement of material science, the general direction of peptide drug delivery system research is to enable oral administration of peptide drugs by improving different drug carriers. Cross-tabulation of the search results showed that most of the novel drug delivery systems were developed for cancer diseases, probably because of the higher targeting and lower immunogenicity of these new drugs (Fig. 3c ). In addition, the development of anti-infective and cardiovascular peptide drug delivery systems is also very popular, which is closely related to the high specificity and in vivo activity of peptides.

In summary, since the advent of insulin nearly a century ago, nearly a hundred peptide drugs have been approved for the treatment of a variety of diseases, including fatal diseases such as cancer and human immunodeficiency virus infection. The development of peptide-based drugs themselves has received increasing attention compared to the development of delivery modes and vaccines (Fig. 3d ). Nowadays, more research is devoted to optimizing and improving these drugs to overcome the defects caused by their physicochemical properties and other factors. As an innovative treatment option, peptides are widely used in a variety of diseases, bringing hope and light to patients. In addition, peptides as a drug delivery and treatment strategy have different value in different drug delivery systems. Although published and ongoing peptide-based therapeutic research has generated encouraging data, it is still a difficult task to translate these results into clinical success due to species differences, production technology, cost and other factors.

Peptide-based drug market & clinical trial

Over the past two decades, the number of approved peptide drugs has surpassed 60, with more drugs undergoing global approval processes (Fig. 4a ). Based on the currently approved peptide drugs, the majority belong to the agonist category, and the most commonly targeted indications are associated with endocrinology, metabolism, and oncology (Fig. 4b–d ). According to a research report by The Business Research Company, sales in the peptide market are projected to grow from $41.44 billion in 2023 to $45.66 billion in 2024, at a compound annual growth rate (CAGR) of 10.2%. The therapeutic peptide market is expected to experience rapid growth in the coming years. By 2028, this figure is forecasted to increase to $68.83 billion, with a compound annual growth rate (CAGR) of 10.8%. In 2023, North America emerged as the largest region in the therapeutic peptide market, while the Asia-Pacific region is anticipated to demonstrate the fastest growth during the forecast period. One contributing factor to this growth may be the rising prevalence of chronic diseases, which is driving the demand for peptide therapies. From a US-based agency, in January 2023, in individuals aged 50 and above, the number of people with chronic diseases in 2020 is projected to double by 2050. 59 Peptide therapies are instrumental in both preventing and treating certain chronic diseases, thus the anticipated increase in the prevalence of chronic diseases is expected to drive the development of the peptide therapy market during the forecast period. As evidenced by sales statistics for the first half of 2023 (Table 1 ), semaglutide continued to lead global sales of peptide drugs in the first half of 2023 ($90.217 billion). Following closely behind was the GLP-1 RA dulaglutide ($37.896 billion), with the top 8 drugs by sales all used for diabetes treatment. Carfilzomib, a proteasome inhibitor used for the treatment of relapsed or refractory multiple myeloma, ranked 9th. Romiplostim, used for the treatment of immune thrombocytopenia, ranked 10th. Moreover, statistical data on the U.S. pharmaceutical expenditure market in 2023 revealed that semaglutide ($38.6 billion) is the new top overall drug among the top 25 highest-spending medications. This underscores the indispensable role peptide drugs play in the pharmaceutical market. 60 Fig. 4 Peptide drugs market and clinical trials analysis. a Distribution of peptide-based drugs approval times from 2004 to 2024. Over the past two decades, the number of peptide drugs approved by the FDA has varied significantly across different time periods, with the highest number of approvals occurring between 2020 and 2023. b Distribution of peptide-based drugs indication from 2014 to 2024. The largest proportion targets rare diseases, followed by cancer and diabetes mellitus along with its complications. c Distribution of peptide-based drugs route of administration from 2014 to 2024. Subcutaneous injection remains the most prevalent method. d Distribution of peptide-based drugs function from 2014 to 2024. A diverse array of therapeutic roles, including metabolic regulation and hormone modulation. e Distribution of peptide-based drugs indication in clinical trial phase III. peptide drugs related to diabetes mellitus constitute the majority of indications. f Distribution of peptide-based drugs route of administration in clinical trial phase III. The variety of administration routes in Phase III clinical trials is extensive; however, subcutaneous injection continues to dominate as the preferred method of delivery Table 1 Top 10 selling peptide-based drug in 2023 H1 No. Name Brand Names Indication Company 1 Semaglutide Ozempic Diabetes Novo Nordisk 2 Dulaglutide Trulitciy Diabetes Eli Lilly 3 Semaglutide Wegovy Weight Novo Nordisk 4 Tirzepatide Mounjaro Diabetes Eli Lilly 5 Semaglutide Rybelsus Diabetes Novo Nordisk 6 Insulin NovoRapid Diabetes Novo Nordisk Aspart 7 Insulin Humalog Diabetes Eli Lilly Lispro 8 Liraglutide Saxenda Weight Novo Nordisk 9 Insulin Lantus Diabetes Sanofi Glargine 10 Carfilzomib Kyprolis Multiple myeloma AMGEN

In 2023, an analysis of the peptide market share revealed that the metabolic system dominated the market with a revenue share of 37.80%. This underscores the significant importance of peptide therapy in the treatment of diabetes that over 1.31 billion people will have diabetes. 59 Additionally, an estimated 44.7% of adults are unaware of their diabetic condition. 61 On the other hand, the global objective is to curb the increase in diabetes and obesity by 2025, indicating a continued growth in global demand for such drugs. With advancements in new theories, technologies, and materials, the development of peptide drugs has undergone a historic transformation in the post-21st century, becoming more efficient. This has resulted in an increase in the number of approvals and clinical trials of peptide drugs, not only for diabetes but also for various other indications. Literature searches from 2020 to 2024 suggest that tumor research has surpassed diabetes as a key area for peptide drug development (Fig. 3 ).

From 2014 to 2024, a total of 28 drugs will be approved for marketing, indications for ranking the top three include rare diseases (7/29). Diabetes mellitus and its complications (5/29) and cancer (5/29). The functions of these drugs are mainly distributed as multiple agonists (2/29), agonists (8/29), inhibitors (5/29) and antagonists (3/29) (Table 2 , Fig. 4a–d ). Currently, 38 peptide drugs are in phase III clinical trials and are expected to enter the market. In addition to traditional diabetes and cancer treatments, the direction of peptide-based drugs discovery is clustered in COVID-19 (4/42), ophthalmology (3/42), weight management (1/42) and so on (Table 3 , Figure 4e ). The analysis of the route of administration revealed an interesting phenomenon. Routes of administration of approved peptide-based drugs are predominantly s.c . (13/29), remainder is i.v . (10/29) and p.o . (5/29). Significant increase in routes of drug administration in drug in phase III clinics. TDDS (4/42) as well as transmucosal drug delivery (5/42) were used to deliver peptide-based drugs (Figure 4f ). The development of new materials and technologies facilitates the selection of more suitable routes of administration for peptide-based drugs. Due to their high specificity and ability to mimic or manipulate natural interactions between biomolecules, peptide drugs have become an important source of innovation in drug discovery, especially as new drug targets continue to emerge. In the future, advances in drug design and synthesis technologies, as well as innovations in drug delivery systems, are expected to improve the stability and bioavailability of peptide drugs, prolong their half-life in the body, reduce dosing frequency and improve patient compliance. We strongly believe that peptide drugs will usher in a safer, more precise and more convenient medical experience. Table 2 Peptide-based drug approved by FDA from 2014 to 2024 No. Name Approval time Mechanism of Action Targets Indications Route of administration Company 1 Albiglutide Tanzeum ® 2014 GLP-1 receptor agonist Glucagon-like peptide 1 receptor T2DM s.c . GLAXOSMITHKLINE LLC 2 Dalbavancin Dalvance ® 2014 Bacterial cell wall synthesis inhibitor Acute bacterial skin and skin structure infection (absssi) i.v . Allergan 3 Oritavancin Orbactiv ® 2014 Inhibit transglycosylation Skin and skin-structure infections i.v . Melinta Therapeutics 4 Vasopressin Vasostrict ® 2014 Vasopressin V2 receptor agonist Vasodilatory shock i.v . Par Sterile Products 5 Dulaglutide Trulicity ® 2014 GLP-1 receptor agonist Glucagon-like peptide 1 receptor T2DM s.c . ELI LILLY AND CO 6 Parathyroid Hormone Natpara ® 2015 Parathyroid hormone 2 (PTH 2) receptor agonist Hypoparathyroidism s.c . NPS Pharms Inc. 7 Grazoprevir Zepatier ® 2016 NS3/4 A viral protease inhibitor Chronic hepatitis c genotype 1 p.o . Merck Sharpe & Dohme 8 Gallium dotatate Ga-68 Netspot ® 2016 Binds to somatostatin receptors Localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients i.v . AAA USA Inc. 9 Lixisenatid Adlyxin ® 2016 GLP-1 receptor agonist T2DM s.c . Sanofi-Aventis 10 Macimorelin Macrilen ® 2017 Growth hormone secretagogue receptor type 1 agonist Adult growth hormone deficiency p.o . Novo Nordisk 11 Voxilaprevir Vosevi ® 2017 NS3/4 A viral protease inhibitor Hepatitis C infections p.o . Gilead Sciences Inc. 12 Etelcalcetide PARSABIV ® 2017 Calcimimetic agent Extracellular calcium-sensing receptor Secondary hyperparathyroidism (HPT) i.v . KAI PHARMS INC 13 Semaglutide OZEMPIC ® 2017 GLP-1 receptor agonist Glucagon-like peptide 1 receptor T2DM s.c . NOVO 14 Abaloparatide Tymlos ® 2017 osteoanabolic agent Parathyroid hormone/parathyroid hormone-related peptide receptor Osteoporosis s.c . RADIUS 15 Plecanatide Trulance ® 2017 Guanylate cyclase-C agonist Guanylate cyclase soluble subunit alpha-2 Chronic idiopathic constipation p.o . SALIX 16 Angiotensin II Giapreza ® 2017 vasoconstrictor Type-1 angiotensin II receptor Low blood pressure i.v . LA JOLLA PHARMA 17 Ivosidenib Tibsovo ® 2018 Isocitrate dehydrogenase-1 inhibitor Acute myeloid leukemia (aml) p.o . Servier 18 Lutetium Lu 177 dotatate Lutathera ® 2018 Radioligand Therapeutic Agent Somatostatin receptor Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) i.v . AAA USA INC 19 Afamelanotide SCENESSE ® 2019 Melanocortin 1 Receptor (MC1-R) Agonists Melanocyte-stimulating hormone receptor Erythropoietic protoporphyria s.c . CLIVUNEL INC 20 Bremelanotide Vyleesi ® 2019 agonist of melanocortin receptors Melanocyte-stimulating hormone receptor/Adrenocorticotropic hormone receptor Hypoactive sexual desire disorder s.c . PALATIN TECHNOLOGIES 21 Gallium ga-68 gozetotide Gallium Ga-68 PSMA-11 ® 2019 Radioligand Therapeutic Agent Somatostatin receptor Radiodiagnostic agents for growth inhibitor receptor-positive neuroendocrine tumors i.v . UIHC PET IMAGING 22 Gallium Ga-68 gozetotide Gallium Ga-68 gozetotide ® 2020 Binds to prostate-specific membrane antigen (PSMA) Prostate-specific membrane antigen positive tumors i.v . University of California, Los Angeles 23 Copper Dotatate Cu-64 Detectnet ® 2020 Binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2) Somatostatin receptor positive neuroendocrine tumours i.v. Radiomedix 24 Setmelanotide Imcivree ® 2020 Melanocortin 4 Receptor Agonists melanocortin 4 (MC4) Rare genetic obesity s.c . RHYTHM 25 Voclosporin Lupkynis ® 2021 CaN inhibitors (calcineurin inhibitors) CaN calcineurin In combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis p.o . Aurinia 26 Melphalan Flufenamide Pepaxto ® 2021 DNA inhibitors DNA Multiple myeloma i.v . Oncopeptides AB 27 Lonapegsomatropin-TCGD Skytrofa® 2021 Release somatotropin, growth hormone receptor agonist Growth failure s.c . Ascendis Pharma 28 Odevixibat Bylvay® 2021 Ileal sodium/bile acid transporter (IBAT) inhibitor Cholestatic pruritus p.o . Albireo 29 Dasiglucagon Zegalogue ® 2021 GCGR agonists (glucagon receptor agonists) GCGR The treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and above s.c . Zealand Pharma 30 Pegcetacoplan Empaveli ® 2021 C3 inhibitor C3 Treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) s.c . Apellis Pharms 31 Difelikefalin Korsuva ® 2021 κ opioid receptor κ opioid Treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis (HD) i.v . CaraTherapeutics 32 Vosoritide Voxzogo ® 2021 NPRB agonist NPRB Chondrodysplasia in children s.c . Biomarin Pharm 33 Daridorexant Quviviq ® 2022 OX1R antagonist (orexin receptor 1 antagonist) OX2R antagonist (orexin receptor 2 antagonist) OX1R &OX2R The treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance p.o . IDORSIA 34 Lutetium 177Lu vipivotide tetraxetan Pluvicto ® 2022 Radioligand Therapeutic Agent PSMA prostate cancer-specific membrane antigen Metastatic denervation-resistant prostate cancer i.v . AAA USA NOVARTIS 35 Tirzepatide Zepbound ® 2022 GIP and GLP-1 dual agonists GIPR&GLP-1R T2DM s.c . Eli Lilly & Co. 36 Terlipressin Terlivaz ® 2022 AVPR1A agonist AVPR1B agonist AVPR2 agonist AVPR1A&AVPR1B &AVPR2 Improvement of renal function in adult patients with hepatorenal syndrome (HRS, hepatorenal syndrome) with rapidly declining renal function i.v . MALLINCKRODT IRELAND 37 Rezafungin Rezzayo ® 2023 1,3-β-Glucan synthase inhibitor 1,3-beta-glucan synthase Treatment of candidemia and invasive candidiasisin patients 18 years of age and older who have limited or no alternative options i.v . Cidara Therapeutics 38 nirmatrelvir and ritonavir Paxlovid ® 2023 Protease inhibitors: CYP3A inhibitors (cytochrome P450 family member 3A family inhibitors) SARS-CoV 3CL pro inhibitor (SARS coronavirus 2-3C-like protease inhibitor) CYP3A & SARS-CoV-2 3CL pro Treatment of COVID-19in adults who are at high risk for progression to severe COVID-19, including hospitalization or death p.o . PFIZER 39 Trofinetide Daybue ® 2023 IGF-1R agonist Insulin-like growth factor-I receptor (IGF-1R) Treatment of Rett syndrome in adults and pediatric patients 2 years of age and olde p.o . ACADIA PHARMS INC 40 Flotufolastat F 18 Posluma ® 2023 PSMA Modulator (Prostate Cancer Specific Membrane Antigen Modulator), PET imaging (positron emission tomography enhancement) PSMA (Prostate Cancer Specific Membrane Antigen), visualized by binding to PSMA-expressing cells (e.g. prostate cancer cells). Prostate cancer i.v . Blue Earth Diagnostics 41 Motixafortide Aphexda ® 2023 CXCR4 antagonist CXCR4 First innovative drug targeting stem cell mobilization in multiple myeloma s.c . BioLineRx 42 Zilucoplan Zilbrysq ® 2023 CXCR4 antagonist gMG targets C5 complement Adult patients with generalized myasthenia gravis (gMG) who are positive for anti-acetylcholine receptor (AChR) antibodies s.c . UCB INC Table 3 Peptide-based drug in clinical phase III R&D Code Name Target Indications Route of administration Clinical Trial ID ACT-1 Granexin 738 GJA1 Diabetic Foot Ulcers (DFUs) Topical-gelling agent NCT02667327 CJC-1134-PC Albenatide 739 GLP-1R T2DM s.c . CTR20202681 - Ambervin IL-6 COVID-19 i.m . NCT05656495 FE 203799 Apraglutide 740 GLP-2 R Short Bowel Syndrome (SBS) s.c . NCT05018286 - BRM-421 741 BRM-421 Dry Eye Syndrome (DES) eye drops NCT05695781 AM-833 Cagrilintide 742 CGRP R T2DM s.c . NCT05669755 TD-1792 Cefilavancin 743 Antibiotic Bacterium infection i.v . NA DD-04107 DD-04107 248 synaptotagmin-1 Neuropathic pain Topical lotion, s.c. EUCTR2022-001374-60-ES XW-003 Ecnoglutide 744 GLP-R Weight management s.c . NCT05813795 XW-003 Ecnoglutide 744 Thyroid Hormone Receptor Type 2 diabetes s.c . NCT05680155 AZP-3601 Eneboparatide 745 PTH-1R Hypoparathyroidism s.c . NCT05778071 MK-0616 Elicitide chloride 218 PCSK9 Arteriosclerosis p.o . NCT06008756 FE-106483 VA-106483 Fedovapagon 746 V2R Nocturia p.o . NCT02637960 ZP-1848 Glepaglutide 747 GLP-R Short bowel syndrome s.c . EUCTR2020-005502-25-NL NN1535 Insulin icodec 748 INSR T2DM s.c . NCT05259033 JTA-004 JTA-004 749 unknown Osteoarthritis Intra-articular injection EUCTR2019-000796-16-CZ AZP-531 Livoletide 750 ghrelin Prader-willi syndrome s.c . EUCTR2018-003062-13-NL LP-17/LR-12/LR-17/TREM-1 inhibitors Nangibotide 751 TREM1 COVID-19, Virus identified i.v . EUCTR2020-001504-42-ES NA-1 Nerinetide 752 PSD-95 Acute ischemic stroke i.v . EUCTR2020-002360-30-NL MSI-78 Pexiganan 753 Antibiotic Type2 diabetes Emulsions NCT01594762 PL-5 Peceleganan 429 Antibiotic Diabetic foot ulcer Aerosol CTR2300071255 BIM-28131 BIM-28163 Relamorelin 754 Ghrelin Receptor/GHSR Diabetic gastroparesis s.c . EUCTR2017-002177-20-RO P2K PENIEL 2K、PENIEL-2000 Remedisc 755 TGF-β1 Degenerative disc disease injection NCT05516992 LY 3437943 Retatrutide 756 Glucagon R T2DM s.c . NCT05929079 rE-4 Exenatide-4 757 GLP-1R Type2 Diabetes s.c . NCT03239119 PTG-300 Rusfertide 758 Hepc Anemia Polycythaemia vera s.c . NCT06033586 SNP ACTH (1-39) SNP-ACTH SNP-ACTH9 (1-39) 759 ACTH receptor Idiopathic membranous nephropathy Primary Membranous Nephropathy s.c . NCT05696613 - SR-0379 760 Akt-1\Class I-PI3K\ mTOR Skin ulcer Transdermal drug delivery JRCT2031210266 CB-183315 CB-315 Surotomycin 418 unknown Infection Clostridium difficile infection p.o . EUCTR2012-000252-34-AT BI-456906 Survodutide 761 Glucagon R T2DM s.c . NCT06066528 MIM-D3 Tavilermide 762 Trk Dry eye syndromes Eye drops NCT05848128 RGN-259 Timbetasin 763 thymosin beta 4 Dry eye syndrome Eye drops NCT05555589 NA 831 Traneurocin 764 GR COVID-19 Virus identified p.o . NCT04540185 AMG 386 Trebananib 765 ANGPT1/ANGPT2 Ovarian cancer i.v . NCT01281254 ANF-95-126 ANP 95126 ANP-95126 Ularitide 766 NPR1 Decompensated heart failure i.v . EUCTR2006-002403-13-FI AT-406 DEBIO-1143 Xevinapant 767 IAP Head and Neck Cancer p.o. NCT05386550 YKYY-017 YKYY-017 468 SARS-COV-2 S protein COVID-19 Virus identified Nebulized inhalation CTR2300075467 PN-2123555 PN-235 JNJ-2113 IL-23R Plaque Psoriasis p.o . NCT06220604

Advance in peptide-based delivery platforms

The cell membrane serves as a crucial physiological barrier that impedes the passage of therapeutic molecules to their intended target site. CPPs represent a viable approach for enhancing the intracellular uptake of therapeutic molecules, thereby enabling the exertion of therapeutic effects. CPPs facilitate the delivery of various cargoes, including nanocarriers, drugs, and nucleic acids. 62 – 64 CPP-based peptide delivery platforms have emerged as a significant focus of research, and we have summarized the advancements made in their clinical trials, indications primarily include cancer, cardiovascular disease, and imaging (Table 4 ). This chapter examines the advancements in CPP-engineered nanocarriers and research on CPP conjugate drugs. Table 4 CPPs-based delivery platforms in clinical phase No. Name CPPs Cargo Indications Clinical Trial ID Status 1 P28 768 P28 NA Solid tumors NCT00914914 Phase I 2 P28 768 P28 Non-HDM2-mediated peptide ihibitor of P53 CNS malignancies NCT01975116 Phase I 3 AM-111 769 TAT JBD20 (D-JNKI-1) Hearing loss NCT02809118 Phase III 4 KAI-9803 770 TAT δPKC inhibitor Myocardial infarction NCT00785954 Phase II 5 KAI-1678 771 TAT Εpkc inhibitor Postherpetic neuralgia postherpetic neuralgia spinal cord injury postoperative NCT01106716 Phase II 6 AVB-620 772 ACPPs Cy5 and Cy7 Tumor imaging NCT02391194 Phase I 7 XG-102 773 TAT JBD20 (D-JNKI-1) Postoperative ocular inflammation NCT02235272 Phase III 8 DTS-108 774 a highly charged oligopeptide of human origin SN38 Tumour NA Phase I 9 ALRN-6924 775 , 776 a cell-penetrating stapled alpha-helical peptide structure undisclosed Palbociclib Solid tumour NCT02264613 Phase II 10 ALRN-6924 775 , 776 a cell-penetrating stapled alpha-helical peptide structure undisclosed Cytarabine Acute myeloid leukemia and advanced myelodysplastic syndrome NCT0909972 Phase I 11 ALRN-6924 775 , 776 a cell-penetrating stapled alpha-helical peptide structure undisclosed Paclitaxel Advanced, metastatic or unresectable solid tumors NCT0725436 Phase I 12 PsorBan 777 R7 cyclosporin A Psoriasis NA Phase IIb discontinued 2003 13 AZX100 778 , 779 PTD4 HSP20 phosphopeptide Scar prevention/ reduction NCT00892723 Phase II 14 RT001 780 , 781 MTSsss Botulinum toxin A Lateral canthal Line Crow’s feet Facial wrinkles NCT01940991 Phase II 15 RT002 782 TransMTS botulinum toxin A Glabellar lines NCT02303002 Phase I/II 16 NA TransMTS Daxibotu-linumtoxin A Cervical dystonia NCT02706795 Phase II 17 AVI-4658 783 NA Duchenne muscular dystrophy NA NCT02255552 Phase III 18 AVI-5126 784 , 785 (R-Ahx-R) 4 Phosphorodia-midate morpholino oligomers (PMOs) Cardiovascular disease Coronary artery bypass NCT00451256 Phase II 19 AEM-28 786 a high-affinity lipid-associating peptide (DWLKAFYDKVAEKLKEAF) An arginine-rich apo E receptor bind-ing domain (residues 141-150 LRKLRKRL-LR) Type II hyperlipoproteinemia NCT02100839 Phase I/II 20 PEP-010 787 , 788 NA Interfering peptide Metastatic solid tumor cancer NCT04733027 Phase I

Peptide-drug conjugates

Introduction of peptide-drug conjugates (PDCs)

In cancer treatment, the inability to distinguish tumor cells from normal cells has led to substantial side effects with current drugs. An innovative solution is Antibody-Drug Conjugates (ADCs) - monoclonal antibodies linked to cytotoxic drugs. 65 ADCs enhance targeting and reduce side effects. However, ADCs have limitations like complex pharmacokinetics, side effects, and ineffective drug release. 66 To address these issues, PDCs have emerged as a novel approach. Though PDCs and ADCs share conceptual similarities as targeted antitumor therapies, they differ markedly in structure and pharmacological behavior. 67

Unlike bulky ADCs, PDCs feature short CTPs instead of antibodies, enabling specific binding to receptors overexpressed on cancer cells. 68 , 69 Owing to their low molecular weight, typically just a few kilodaltons, PDCs demonstrate superior tumor penetration and lower immunogenicity compared to ADCs, which generally exceed 150 kilodaltons. 63 While ADCs utilize hepatic metabolism, PDCs employ renal clearance. The conformational freedom of PDCs’ abbreviated peptide sequences also permits the introduction of non-natural amino acids. This facilitates cyclic peptide formation and chemical conjugation to other molecules, expanding PDCs’ targeting potential, stability, and versatility. 70 , 71 With enhanced precision, durability, and adaptability compared to earlier generations of ADCs, PDCs have emerged as highly promising next-generation targeted cancer therapies. 63 , 67

The composition of PDCs involves three components: 1) the cell-targeting peptide, 2) a linker, and 3) the cytotoxic payload. 63 CTPs are selected peptides that can specifically target protein receptors overexpressed on tumor tissues, allowing drug delivery vehicles like PDCs to be directed to target cells. 69 , 72 , 73 These peptides often have high binding affinity, in the nanomole range, to their receptors. 27 Their binding is affected by their secondary structure, which must be retained when attaching a linker. 74 Common cell-targeting examples bind integrins and CD13 receptors on tumors, like the RGD and NGR peptides. 75 , 76 CTPs can be linear or cyclic/stapled, with cyclic versions having improved stability and binding, like a cyclic RGD peptide targeting glioblastomas. 63 , 75 Some CTPs act as CPPs, transporting compounds into cells, with cationic ones having less specificity than anionic and may produce unwanted toxicity to normal cells at higher peptide concentrations. 77 Among various CPPs, arginine-rich peptides are the most widely used. Recently, it is reported that the specific cell penetration, toxicity, and in vivo biocompatibility of CPPs can be balanced by designing peptides with optimal arginine residue lengths, enlightening us that perhaps CPPs contain other possibilities of PDCs. 78 Besides, advances in technologies such as proteomics, phage display, and mRNA display have enabled the discovery and design of a growing repertoire of targeted peptides, propelling PDC development. 79 , 80

Linkers are used to connect the cell-targeting peptide to the cytotoxic drug payload. Ideal linkers are stable in circulation to prevent premature drug release and toxicity. 74 Cleavable linkers release drug via chemical (e.g. acid, glutathione) or enzyme triggers in the tumor environment. 81 Non-cleavable linkers rely on carrier breakdown to release an intact drug-linker complex to kill cells. 82 Cleavable linkers allow more controlled drug release but non-cleavable linkers can have increased stability. 27 , 83 The choice of linker depends on the desired design and mechanism of action of the targeted therapeutic. For instance, oxime-linked anthracycline-peptide conjugates have demonstrated many advantages in PDCs development, including ease of direct synthesis; the conjugation reaction proceeds in excellent yields; and the autofluorescence of anthracyclines provides a basis for selecting appropriate ones. 84 Besides, it is worth noting that stimuli-responsive linkers can also improve cell-targeting peptide targeting. 85

Cytotoxic drug payloads used in PDCs often have limitations like poor pharmacokinetics when used alone. Attaching them to targeting peptides helps overcome issues and enhances their therapeutic window. 86 Desired drug payloads have high potency with IC 50 values in the nanomolar range, stability in circulation, and a point for attaching a linker. 68 Examples include doxorubicin (DOX), paclitaxel (PTX), and mertansine. 87 Radionuclides like 177 Lu-dotatate are also increasingly used as payloads, enabled by peptide targeting. Radionuclides are repurposed FDA-approved agents that allow imaging to precisely locate tumors and monitor progression by PET or SPECT. 88 The high selectivity of peptides for receptors gives excellent tumor contrast with minimal off-target effects. Useful radionuclides include positron emitters like 68 Ga and 18 F for PET scanning, 89 and gamma emitters like 123 I and 99m Tc for SPECT. 90 Bifunctional chelators like DOTA and DTPA link radioisotopes to targeting vectors. 91 Overall, the versatility of PDCs allows targeted delivery of diverse cytotoxic and radionuclide payloads.

Up to now, several PDCs have entered clinical evaluation (Table 5 ), with two receiving regulatory approval—Lutathera (Lutetium Lu-177 Dotatate) in 2017 and Pepaxto (melphalan flufenamide) in 2021. 92 , 93 Novartis’ Lutathera utilizes a somatostatin-targeting peptide and the radionuclide 177 Lu to treat gastrointestinal and pancreatic neuroendocrine tumors. 94 Oncopeptides developed Pepaxto, comprising alkylating agent-conjugated peptides targeting aminopeptidase for relapsed/refractory multiple myeloma, though it was later withdrawn from the U.S. market due to disappointing efficacy. 95 In addition to the approved PDCs discussed above, two of the most advanced PDCs under development are SNG1005 and AEZS-108. SNG1005 is a brain-targeted PDC that has demonstrated promising clinical efficacy in treating brain metastases from breast cancer, and is currently in Phase 3 clinical trials. 96 AEZS-108 is a PDC that is being evaluated in trials for the treatment of proliferative fibrotic prostate cancer. 96 , 97 Table 5 Peptide-drug conjugates drug in clinical trial No. Name CTPs Drugs Linker Indications Clinical Trial ID Status 1 ANG1005 789 (paclitaxel trevatide) Angiopep-2 Paclitaxel Succinic- acid Leptomeningeal metastases NCT03613181 Phase III 2 GRN1005 790 Angiopep-2 Paclitaxel Succinic- acid Breast cancer brain metastases; non-small cell lung cancer (nsclc) with brain metastases NCT01679743 Phase II 3 BT1718 791 (Bicycle Therapeutics) MT1-MMP binder Mertansine (DM1) Disulfide Advanced solid tumours;non-small cell lung cancer;non-small cell lung sarcoma NCT03486730 Phase I/II 4 BT5528 792 EphA2 binder MMAE Amide Solid tumors EphA2-positive NSCLC NCT04180371 Phase I 5 BT8009 118 (Bicycle Therapeutics) Nectin-4- binder MMAE Amide Solid tumors NCT04180371 Phase I/II 6 TH1902 793 TH19P01 Docetaxel Succinic acid Solid tumors NCT04561362 Phase I 7 TH1904 794 TH19P01 Doxorubicin Succinic acid Solid tumors NCT04706962 Phase I 8 G-202 795 (mipsagargin) DγEγEγEγE Thapsigargin Amide Solid tumors NCT02381236 Phase II 9 NGR015 796 CNGRCG (1,5SS)/RGD hTNF Amide Malignant pleural mesothelioma NCT01098266 Phase III 10 Ttf-ngr 797 GNGRAHA/NGR Ttf Amide Malignant solid tumors lymphomas NCT02902237 (2020) Phase I 11 PEN-221 798 fCYwKTCC (2,7 SS) DM-1 Disulfide Neuroendocrine tumors carcinoma Small cell lung cancer NCT02936323 (2021) Phase I/II 12 Zoptarelin doxorubicin 799 D-Lys6-LHRH Doxorubicin Amide Pre-treated advanced/metastatic recurrent endometrial cancer NCT01767155 (2020) Phase III 13 CBP-1008 800 CB-20BK MMAE Amide Advanced solid tumor NCT04740398 (2022) Phase I 14 CBP-1018 671 LDC10B MMAE Amide Lung tumor NCT04928612 (2022) Phase I 15 SOR-C13 801 folate MMAE Amide Advanced malignant solid neoplasm NCT03784677 (2021) Phase I 16 [18 F]AlF-NOTA-octreotide 802 octreotide/RGD 18 F NOTA PET or GEP-NETs Neuroendocrine tumors NCT04552847 (2020)/ NCT03883776 (2020) Phase I/II/III 17 [18 F]Fluciclatide 800 RGD 18 F PEG PET imaging NCT00918281 (2014) Phase II 18 [18 F]RGD-K5 160 cyclo (RGDfK) 18 F NOTA PET imaging NCT03364270 (2020) Phase II 19 68Ga-NODAGA-E [cyclo (RGDyK)]2 803 E [cyclo (RGDyK)]2 68 Ga NODAGA PET imaging NCT03271281 (2021) Phase II 20 68Ga-NOTA-BBN-RGD 75 cyclo (RGDyK) and BBN 68 Ga NOTA PET imaging NCT02747290 (2016) Phase I 21 90Y-DOTATOC 804 3Tyr-octreotate /DOTATOC 90Y DOTA PRRT NCT03273712 (2019) Phase II 22 99mTc-3PRGD2 805 3Tyr-octreotate/RGD 99mTc 3PRGD2 Breast cancer NCT02723760 Phase I 23 111In-DTPA-octreotide 806 3Tyr-octreotate 111In DTPA Brain and central nervous system Tumors PET imaging NCT00002947 (2014) Phase I 24 CBX-12 807 (Cybrexa Therapeutics) (alphalex-exatecan) a pH-sensitive peptide Exatecan Advanced solidtumors NCT05691517 Phase l/ll 25 OPD5 808 (Oncopeptides AB) Melflufen an aminopeptidase-targeting linkage Relapsed multiplemyeloma NCT04918511 Phase I 26 TH1902 809 (Theratechnologies) TH19P01 Docetaxel/sudocetaxel a cleavable ester Triple-negativebreast cancer NCT04706962 Phase I 27 phosphorodiamidate morpholino oligomer-cell-penetrating peptide 810 (EDO-51、PGN-EDO23、PGN-EDO51) Oligonucleot-ide Duchenne dystrophy NCT06079736 Phase II 28 bevonescein 811 (ALM-488) RGD Fluorescein Head and neck injury NCT05377554 Phase III 29 EP-100 812 (onvitrelin ucalontide) CLIP-71 LHRH none Solid tumors NCT01485848 Phase II 30 BGC-0228 96 CD44 TOP1 inhibitor Advanced solid tumor CTR20220194 Phase l 31 SC-101 813 Nectin-4 binder microtubule inhibitors Advanced solid tumor NCT06220838 Phase l 32 AEZS-108/ZEN-008/AN-152 814 [d-Lys6] LHRH doxorubicin a glutaric acid spacer Endometrial Cancer NCT01767155 Phase III

Current research status: unveiling diverse peptide-drug conjugates

As the next generation of smart drug conjugates, the impending wave of PDCs brings new hope for targeted therapy, especially in the field of anti-tumor. 27 , 67 In the sections below, we detail the various PDCs targeting tumors that have been developed so far, categorized by the targets targeted by their cell-targeting peptide moieties.

Integrin-targeting PDCs

Integrin-Targeting PDCs have emerged as an innovative therapeutic strategy, especially those targeting the α v β 3 integrin subtype. 98 Recognizing the pivotal roles of integrins, particularly their widespread overexpression across numerous cancer types, researchers have tapped into their potential for targeted drug delivery using PDCs. 99 RGD peptides have taken center stage owing to their remarkable binding specificity for α v β 3 integrins. 100 Strategically integrated into PDCs as guiding entities for cytotoxic payloads like DOX and camptothecin (CPT), RGD peptides enable enhanced therapeutic effects by precisely targeting cancer cells with elevated α v β 3 expression. 75 Further complementing PDCs design sophistication are innovative linkers, a cleverly designed example utilizes albumin metabolism to mediate apoptosis and trigger the expression of Caspase-3, which allows the PDC to remain persistently activated, enabling payload accumulation and subsequent bystander killing effects. As caspase-3 becomes continuously upregulated within the tumor, on-site cellular apoptosis is exacerbated. The sustained caspase-3 upregulation, mediated by albumin metabolism, enables continuous PDC activation and payload buildup, leads to enhanced bystander effects and further promotes in situ tumor cell apoptosis. 101

Furthermore, α v β 6 integrin-targeting PDCs, specific to pancreatic ductal adenocarcinomas, hold promise in treating pancreatic ductal adenocarcinomas (PDAC). 102 Taken SG3299 as an example, formed by conjugated the DNA-binding pyrrolobenzodiazepine (PBD) payload SG3249 (tesirine) was to an α v β 6 -specific 20mer peptide from foot-and-mouth disease virus (FMDV) VP1 capsid protein, this α v β 6 -targeted PDC SG3299 demonstrated significantly greater toxicity (up to 78-fold) against α v β 6 -expressing cells compared to the non-targeted PDC SG3511 at equimolar doses. In in vivo xenograft studies, SG3299 eliminated established (100 mm 3 ) Capan-1 PDAC human xenografts and significantly prolonged mouse survival, 103 exemplifying the precision and potential therapeutic impact of α v β 6 -directed PDCs for pancreatic cancer.

EGFR-targeting PDCs

Epidermal Growth Factor Receptor (EGFR) is a pivotal transmembrane receptor governing cancer cell signaling, represents an attractive molecular target for cutting-edge precision therapeutics. 104 The innovative development of EGFR-targeting PDCs is strategically designed to leverage the overexpression of the EGFR in diverse cancer types. To enhance cellular uptake and facilitate unique photoactivated cytotoxic effects, both linear and cyclic EGFR-binding peptides are incorporated to selectively targeting EGFR-dysregulated cancers for more effective treatment. 67 For example, a linear EGFR-binding peptide (YHWYGYTPEVI) conjugated with phthalocyanine, achieving heightened uptake and photoactivated cytotoxicity against epidermoid carcinoma cells. 105 Besides, a cyclic EGFR-binding peptide (CMYIEALDKYAC) elicited preferential accumulation in EGFR-overexpressing malignancies, which in turn produced significantly higher photocytotoxicity and effectively inhibited tumor growth after photodynamic therapy. 106 Recently, to develop targeted therapies for cancers with overexpression of EGFR due to kinase domain mutations like L858R/T790M that promote cancer cell growth, studies have explored novel PDCs of WNWKV and LARFFS binding to wildtype and mutant EGFR. In lung cancer cells expressing wildtype or double mutant EGFR, WNWKV conjugates showed greater anticancer potency than LARFFS conjugates, while unconjugated LARFFS displayed poor binding. The enhanced antiproliferative effects of WNWKV conjugates highlight their potential for targeting EGFR mutants like L858R/T790M, providing guidance for developing therapies against EGFR receptors. 107

HER2-Targeting PDCs

Capitalizing on HER2 receptor overexpression in cancers like breast and lung, HER2-targeting PDCs have also emerged as an impactful focus. 108 For example, a Cyclo-GCGPep1 peptide was modeled after the trastuzumab-HER2 interface and conjugated it with CPT, creating a PDC with potent antiproliferative effects on HER2 + cells. Additionally, a novel HER2 PDC was developed by conjugating a homodimer HER2-targeting peptide (composed of two identical binding ligands connected via a linker) with the cytotoxic agent DOX using an acid-cleavable hydrazone linker. The PDC exhibited significantly enhanced tumor-targeting capabilities and anticancer activities, particularly against HER2 + tumors. Meanwhile, the dimerization of the HER2-binding peptide ligand led to increased receptor affinity and cellular internalization compared to the monomeric counterpart. 109 Similar examples include a novel PDC obtained by fusing the N-terminal sequence of the second mitochondria-derived activator of caspases (SMAC) with P1, followed by conjugation to a CPT molecule. Which exhibited outstanding in vitro antitumor activity against three HER2-positive cell lines, comparable to CPT alone. 110 To harness the HER2 axis, innovative computer-designed bispecific fusion peptides with superior HER2 + binding has also been reported. 67

D) TfR-targeting PDCs

Transferrin Receptor (TfR)-targeting PDCs present another avenue for selective drug delivery by targeting the overexpressed TfR in cancer cells. 111 For instance, a recently reported PDC was designed and synthesized by using N-succinimidyl-3-maleimidopropionate (SMP) as a crosslinker to connect the TfR targeting peptide analogue BP9a (CAHLHNRS) and DOX. Which exploits BP9a mediated TfR recognition for selective delivery of doxorubicin to malignant cells and enhances therapeutic index and mitigate off-target toxicity to normal tissues. 112 In addition, the development of a novel T7-SN-38 PDC using the affinity of HAIYPRH (T7) peptide to TfR overexpressed on blood-brain barrier and glioma cells has also been recently reported. 113

E) SORT1-targeting PDCs

Recent advancements spotlight the SORT1 receptor as a promising target that with predominant overexpression observed across numerous malignant tumor types. 114 By exploiting the SORT1 internalization function, a peptide (TH19P01) was developed. In vitro, although the TH19P01 peptide itself exerted no antiproliferative or apoptotic effects when tested on TNBC-derived MDA-MB-231 cells, the docetaxel-TH19P01 conjugate (TH1902) demonstrated potent antiproliferative and antimigratory activities. 115

VEGFR-Targeting PDCs

VEGFR-targeting PDCs, adopting an antiangiogenic approach, couple VEGFR-targeting peptides with lytic peptides, showing potential toxicity to hepatoma cells. 116 For instance, by conjugating a VEGFR-targeting peptide (QKRKRKKSRYKS) to a lytic peptide (KLUKLUKKLUKLUK), not only can it target and inhibit VEGFR on the cell surface to effectively suppress angiogenesis in tumor tissues, but it has also demonstrated superior in vivo antitumor efficacy compared to the traditional drug DOX in a VX2 rabbit tumor model with a favorable safety profile. 117 Besides, this tailored PDC exhibited potential hepatoma cell toxicity, showcasing enhanced anticancer efficacy through specific VEGFR targeting.

Diverse targeting strategies

Furthermore, CTPs continue to diversify beyond conventional receptors, with emerging efforts directed against unconventional antigens like poliovirus receptor-related protein 4 (Nectin-4), 118 somatostatin receptor 2 (SSTR2), 119 gonadotropin releasing hormone receptor (GnRHR), transient receptor potential vanilloid subfamily member 6 (TPRV6), 120 glypican-3 (GPC3), 121 E-selectin, 122 melanocortin-1-receptor (MC1R), 123 receptor tyrosine kinase-like orphan receptor 1 (RORl), 124 Kita-Kyushu lung cancer antigen 1 (KK-LC-1), 125 and Hsp90. 126 For instance, two of the most advanced PDCs under development are SNG1005 and AEZS-108. SNG1005 is a brain-targeted PDC that has demonstrated promising clinical efficacy in treating brain metastases from breast cancer, and is currently in Phase 3 clinical trials. 96 AEZS-108 is a PDC targeting GnRHR, which is being evaluated in trials for the treatment of proliferative fibrotic prostate cancer. 96 , 97 Besides, an ingenious design is an intelligent ultrasound theranostic peptide-porphyrin conjugate (P18-P) that self-assembles into supramolecular structures through cathepsin B (CTSB)-triggered aggregation. After intravenous injection, the multifunctional probe achieves deep tissue penetration due to the penetration sequence of P18-P. More importantly, CTSB-triggered self-assembly greatly extended the retention time, amplifying photoacoustic imaging signals for sensitive CTSB detection, and enhanced sonodynamic therapy activity for oxygen generation, eliciting a specific CTSB-responsive ultrasound therapy. 127 As representatives, these PDCs showcase the versatility of PDC research in addressing specific molecular markers and paving the way for novel therapeutic interventions across various cancer types.

Future prospects of peptide-drug conjugates

PDCs have emerged as a transformative and precise targeted cancer treatment that combines the selectivity of peptides with the cytotoxicity of chemotherapeutic agents, effectively addressing the limitations associated with traditional chemotherapy, expanding the therapeutic window, enhancing efficacy, and redefining targeted therapy. 27 , 63 , 67 , 69 , 128

Despite notable success in clinical use, challenges such as poor stability and a short half-life persist. Looking ahead, the future of PDCs involves the development of PDCs based on humanized antibodies, 129 exploring stimuli-responsive drug release mechanisms, 130 employing computer-aided drug design, 131 exploring diverse receptors or antigens, 132 integrating with immunotherapies and gene therapies to address stability, off-target effects and resistance issues, 133 , 134 and advancing scalable manufacturing processes. 135

CPPs-engineered nanocarriers

The challenge of delivering molecularly targeted therapies to specific regions with precision is a common obstacle in the commercialization of new drugs. Peptides, with their high receptor affinity, low toxicity, design flexibility, and cost-effectiveness, have made peptide-based drug delivery systems a popular area of research. 136 CPPs, also known as protein translocation domains (PTDs), membrane translocation sequences, or Trojan peptides, are a group of cationic peptides consisting of 5-30 residues. 137 , 138 In 1988, Frankel purified the first CPP from a virus with the sequence YGRKKRRQRRR. This peptide exhibited efficient intracellular translocation and was named HIV Tat (transactivating) protein (TAT). 139 TAT was used to create delivery systems for small molecule, nucleic acid and immunotherapy drugs. 140 – 143 Due to technological advancements, a growing number of naturally derived or synthetically produced CPPs have been introduced into the research field. 137 Currently, over 100 CPPs have been identified or synthesized and are structurally categorized as cationic, cyclic, amphipathic, or hydrophobic. CPPs are classified based on their source as follows: (1) naturally occurring protein-derived CPPs, such as penetratin (Pen) and Tat; (2) chimeric CPPs, such as transportan, which is a peptide composed of 14 amino acids from the venom of the yellowjacket wasp (Vespula lewisii) and 12 amino acids from the N-terminus of substance P; and (3) fully synthetic CPPs, such as oligoarginines and peptide nucleic acids (PNAs). 144 , 145

Just as the efficacy of drugs within the body depends on their ability to cross physiological and pathological barriers, such as the phospholipid bilayer, the key to the action of CPPs lies in their transport efficiency. 146 CPPs can facilitate cargo internalization by directly conjugating with the C-terminus of proteins or peptides, creating nanocomplexes through hydrophobic/electrostatic interactions, or covalently linking with nucleic acid molecules. 147 However, the specific mechanisms of internalization are still not well understood. Cellular parameters, cargo characteristics, and CPP physicochemical qualities all impact internalization efficiency. 148 Internalization involves two steps: overcoming the membrane barrier and exiting the endosomes. Two membrane translocation processes are thought to be energy-independent direct translocation and energy-dependent endocytosis. The interaction between cationic CPPs and negatively charged membrane structures, such as glycosaminoglycans, can lead to the formation of pores, inverted micelles, and a ‘carpet model’ during direct translocation. 149 – 151 CPPs, which typically contain arginine and lysine residues, carry a positive charge at physiological pH, enabling electrostatic interactions with negatively charged cell membranes or cargo. Among them, arginine-containing CPPs such as TAT and octa-arginine (R8) have gained a lot of interest. 152 Endocytosis, an energy-dependent process, can be achieved through various mechanisms, including clathrin-dependent endocytosis, lipid raft-mediated endocytosis, and caveolin-mediated endocytosis. Kaplan et al. reported that TAT is internalized via lipid raft-mediated endocytosis, 153 which is influenced by cell membrane features, microenvironmental factors, and cargo characteristics. 154 , 155 Following cellular uptake, cargo must escape the endosome to exert therapeutic effects, as seen with TAT. 156 The internalization and the endosomal release mediated by CPPs is influenced by multiple mechanisms and may vary in different pathological and physiological environments, leading to ongoing debates regarding its specific processes (Fig. 5 ). Fig. 5 Overview of physiological incorporation of peptide-based delivery strategies (including targeting, transmembrane, escape, organelles). There are two major pathways for the incorporation of CPPs including endocytosis pathways and direct penetration pathways. Through endocytosis, CPPs induce membrane concavity, resulting in the formation of endosomes within the cell, while certain CPPs trigger the development of large, irregular macropinocytosomes. In contrast, direct penetration occurs through three distinct mechanisms: First, CPPs can translocate through substantial holes in the lipid bilayer, where the cell membrane forms an extensive pore channel. Alternatively, CPPs may cross the membrane via transient prepores, characterized by smaller-diameter, short-lived openings in the cell membrane. Finally, CPPs can traverse the lipid bilayers through the formation of inverted micelles, offering yet another pathway for cellular entry

To date, FDA has not approved a single CPP or CPP/drug combination, likely due to the inherent challenge of CPPs solely facilitating the accumulation of transmembrane cargo at specific therapeutic target sites. Homing/targeting peptides have become a major avenue of research in peptide-based drug delivery systems to address the need for tumor targeting together with the CPPs (Fig. 6 ). Unlike naturally occurring CPPs, homing/targeting peptides are often identified through display library screening, 157 , 158 with further advances expected to yield more potential homing/targeting peptides. Tumor-homing peptides (HTPs) offer several benefits, including biocompatibility, low cytotoxicity to non-tumor cells, low immunogenicity, and high permeability due to their small size, which form the peptide-based drug delivery system. Additionally, they can be easily modified and redesigned as needed. 159 Delivery systems that have been altered to include homing/targeting peptides have demonstrated impressive outcomes in immunotherapy, radiation, chemotherapy, and photo/photodynamic therapy. 84 , 160 – 166 Several targeting peptides have been developed to bind to receptors that are highly expressed on the surface of tumor cells, including integrins, HER2, and EGFR. Examples of these peptides include the HER2-targeting peptide AHNP, 167 the integrin-targeting peptide iRGD, 168 and the EGFR-targeting peptide GE11. 169 Recent research has also identified a novel CPPs called T3BP. The potential exists for it to bind to the type III transforming growth factor-β receptor (TGFBR3) and provide a novel treatment approach for tumors such as breast, prostate, and colon cancers. 170 See the excellent description of homing peptides and representative CPPs by Eisaku Kondo’s team. 171 We believe that with the assistance of new technologies, homing peptides represent a promising new tool in biomedicine. Fig. 6 Overview of Targeting and Delivery Strategies for Peptide-based Delivery Systems. CPPs enable the efficient translocation of cargo molecules (e.g., drugs, therapeutic proteins, or nucleic acids) across cellular membranes, facilitating their intracellular delivery and therapeutic action within target cells. The another is Targeting peptides. These peptides can specifically recognize various disease-associated targets expressed on the surface of target cells or in the diseased tissue environment. Only a few typical examples of such targets are depicted, serving as illustrations for the diverse range of potential targets that can be exploited by targeting peptides for disease-specific applications. Figure 6 was created with biorender.com

Our paper provides an update on the development of research into targeting specific intracellular organelle peptides. Drug delivery to particular subcellular organelles, such as the Golgi, endoplasmic reticulum, 172 mitochondrial, 173 lysosomal, 174 and nuclear transport, 175 is facilitated by the peptides, which are important in the delivery of drugs, genes, and other relevant fields. In order to transfer VEGF siRNA and ASO into colorectal cancer cells, for example, a study described the construction of multifunctional CPP and nuclear localization signal (NLS) cyclic peptide CSP2 (Cyclo [WWWWGGRRRRGC]). 176 The authors previously published a study on a nanostructure based on a tryptophan and arginine-repeated cyclic peptide (Cyclo [WWWWGGRRRGG]).Another study employed a simple enzyme replacement therapy using poly-arginine and poly-histidine peptides as carriers, successfully facilitating the delivery of lysosomal enzyme α-galactosidase A to lysosomes, offering new insights into the treatment of Fabry disease. 174

New technologies offer opportunities for cardiac targeting and overcoming the blood-brain barrier, which is a challenge for traditional CPPs. Cardiac-targeting peptides are an exciting area of research due to the global prevalence of cardiovascular disorders. 177 Ideally, cardiac drugs should exhibit cardiac selectivity. The Zahidt team used the M13 bacteriophage display library to screen and discover a potential cardiac-targeting peptides with high cardiomyocyte targeting. 178 At the same time, a comprehensive report on the discovery and implementation of cardiac-targeting peptides has been created, 179 which is useful in this industry. The blood-brain barrier (BBB) is a vital natural barrier in the body and is linked to several neurological illnesses. Overcoming the blood-brain barrier to achieve brain-targeted molecular delivery is often a primary challenge faced by many researchers in drug design. In recent years, Nose-to-Brain (N-to-B) delivery has emerged as a novel method for drug delivery system. It offers a non-invasive alternative route for the delivery of macromolecules and serves as a convenient approach for rapid targeting of the central nervous system, bypassing the blood-brain barrier and minimizing systemic exposure. Mentzer and colleagues developed a CGRP inhibitor peptide (34 Pro, 35 Phe) CGRP 27–37, which was then prepared as chitosan microparticles for intranasal delivery in dry powder form. This method prevented peptide degradation and provided some relief for migraines. 180 Another significant approach involves using nanocarriers conjugated with peptides for brain targeting. Nanocarriers can recognize transcytosis receptors on the blood-brain barrier to achieve effective drug delivery. 181 For example, modified PLGA-NPs exhibited enhanced brain uptake and provided better MRI contrast for diagnostic purposes. 182 A hybrid metal nanocarrier system consisting of gold and superparamagnetic iron oxide nanoparticles, coated with carboxymethyl cellulose, has been developed. This system can induce oxidative stress and magnetic hyperthermia upon exposure to alternating magnetic fields when functionalized with integrin-binding peptide (iRDG), offering potential for targeted therapy of brain cancer. 183

Advance of peptide-based therapeutics

Enhancing peptide stability and bioavailability through structural modifications

Introduction to structural modification

Peptide therapeutics, owing to their natural amino acid-based composition, exhibit inherent advantages. However, despite these advantages, peptides face substantial challenges, primarily related to their structural properties. 184 Generally, peptides have two major limitations as therapeutics: poor membrane permeability and instability in vivo. 2 Their size and amino acid composition hinder crossing cell membranes to reach intracellular targets. 185 Moreover, the lack of secondary and tertiary structures makes peptides susceptible to enzymatic degradation. Additionally, their amide bonds are also prone to hydrolysis. These two factors result in short half-lives and rapid elimination in vivo for peptides. 184 These limitations, coupled with the high manufacturing costs associated with peptide drug discovery, create hurdles in their widespread application. To overcome these limitations, structural modifications have emerged as a key strategy. A variety of modification methods (Fig. 7 ) have been widely applied to enhance stability against enzymatic cleavage, improve bioavailability by overcoming biological barriers, and fine-tune specificity for selective interactions with target molecules. 184 Fig. 7 Strategies to improve the physicochemical properties of peptide drugs, including cyclization, conjugation strategies, N-terminal modifications, C-terminal modifications, side chain modifications and backbone modifications

Structural modifications for stability and improved bioavailability

Overcoming the instability against proteolysis and limited bioavailability associated with peptide therapeutics are among the most pressing issues in the field of structural modifications. Various structural modification methods have been applied, and here we provide a brief overview of these approaches and their applications.

A) Backbone modifications

Backbone modifications are the earliest structural modification method in the field that targets the masking or removal of amide bonds in the peptide backbone. When it comes to this approach, the most commonly employed tactics include substituting D-amino acids for L-amino acids, 186 , 187 inserting N-alkylated amino acids, 188 and incorporating β-amino acids or α/β-substituted α‑amino acids. 189 , 190 Each strategy is implemented through different principles to address proteolytic stability issues that often plague native peptides. 191 Substituting metabolically labile L-amino acids with their D-amino acid counterparts enhances resistance to enzymatic degradation, significantly extending the peptide’s half-life. 186 The insertion of N-alkylated amino acids and incorporation of β-amino acids or α/β-substituted α‑amino acids strategically fortify the peptide structure, leading to improved stability. 188 In the process of synthesizing lanthipeptides, the backbone modifications are elegantly presented, for instance, d-amino acids are successful introduced into lanthipeptides via two enzymatic reactions catalyzed by the dehydratase domain of lanthipeptide synthase, 192 showcasing the potency of backbone modifications in overcoming challenges associated with proteolytic instability in peptide therapeutics.

Replacing one or more peptide bonds with an isosteric or isoelectronic substitute are also strategies that modify the peptide’s backbones. The isosters that are most frequently used include azapeptides, retro-inverso peptides, and peptoids, 193 – 195 bringing forth diverse modifications and offering unique functionalities to peptide drugs. Azapeptides have a similar structure to natural peptides, but with the key difference of having a nitrogen atom rather than a carbon atom bonded to the amino group, which makes azapeptides useful synthetic mimics of natural peptides. For instance, a powerful new covalent inhibitor of the SARS-CoV-2 main protease (M pro ) using an azapeptide scaffold capped with a cysteine residue was reported recently, enabling targeted, irreversible labeling of the M pro active site and makes it one of the most potent M pro inhibitors reported so far. 196 Retro-inverso peptides, with reversed N- and C-termini sequences and L- to D-amino acid substitutions, find applications as versatile immunomodulators, anti-inflammatory agents, and more. 197 – 199 Peptoids, featuring N-alkylated glycines, provide flexibility and have applications in cancer, neurological and autoimmune disorders. 200

B) Side chain modifications

Side chain modifications are another strategic maneuver in the enhancement of stability and bioavailability of peptide drugs. The principles underlying this approach involve the replacement of natural amino acids with their analogues during the synthesis of peptides. This substitution seeks to bring about advantages such as the augmentation of binding affinity and target selectivity. 201 Notable applications of side chain modifications include the incorporation of analogues like β-phenylalanine, 202 benzyloxytyrosine, 184 and homoarginine. 203 These modifications have found practical implementation in near-infrared (NIR) dye-peptide conjugates, for instance, it has been reported that the use of acetamidomethylcysteine to replace the cysteine residue in a near-infrared fluorescent dye conjugated with the type I collagen targeting peptide RRANAALKAGELYKCILY successfully disrupted the self-assembly of the peptide and thereby changed the performance of the molecular probe in aqueous solution, ultimately improving the contrast of arthritic joints against the background. 204

C) Peptide cyclization

Among the six peptide drugs approved in 2023, three are cyclic peptide drugs (Rezafungin, Motixafortide and Zilucoplan), emphasizing that cyclic peptides have become an important modality in the development of peptide drugs. 205 – 207 Delving into the peptide cyclization unfolds diverse approaches, most commonly used including head-to-tail, backbone-to-side chain, and side chain-to-side chain. 208 The advantages stemming from peptide cyclization encompass heightened proteolytic stability, 209 , 210 and the facilitation of secondary structure formation. 211 , 212 These principles have been applied tangibly in the development of S-tert-butylation of the free thiol group of cysteine. Which was done in a rationally designed peptide using the evolutionarily conserved γ-core region (GXC-X3-9-C) of the antifungal protein from Aspergillus. 213 S-tert-butylation not only improved stability, but also extended the peptide’s antifungal activity to the mold Aspergillus fumigatus.

A significant advantage of cyclic peptides lies in their pharmacokinetic properties. Specifically, their unique characteristics in stability, hydrophilic/lipophilic balance, cell permeability, etc. make cyclic peptides a key focus for the development of orally bioavailable peptide drugs. 214 Among the currently marketed oral peptides, three are cyclic peptides - Cyclosporine A, Voclosporin, and Desmopressin. The favorable pharmacokinetics conferred by their cyclic structure contributes to their success as orally bioavailable peptide therapeutics. 215 – 217 In addition to these marketed drugs, some recently reported cyclic peptide drugs also show potential. For instance, MK-0616 is an orally bioavailable, renally excreted cyclic peptide inhibitor of PCSK9. In clinical trials, MK-0616 has demonstrated dose-dependent reductions in LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels. Besides, it can lower Lp(a). MK-0616 is currently in Phase 3 clinical trials and shows promise for the treatment of cardiovascular diseases given its oral bioavailability, potent lipid-lowering effects, and renal clearance. 218 Meanwhile, stapled peptides, which are also cyclic peptides in nature, skillfully “stapled” into α-helix and β-sheets shapes, exhibit proteolytic resistance and extended plasma half-life, 219 exemplified by stapled peptides that resemble Helix 1 of the human ACE2 receptor, have shown varying degrees of efficacy in preventing SARS-CoV-2 infection. 220 In addition, cyclized analogues adopted type I β-turn structures achieved by substituting select glycine residues with N-(2-thioethyl) glycine and stapling the peptides using bifunctional reagents was reported. Which yielded cyclic analogues with improved analgesic activity compared to the parent enkephalins after introducing benzyl substituents on the trithiocyanurate stapling reagents. 221 Besides, stapling natural peptides by cross-linking two amino groups via different imidazolium linkers with various α-ketoaldehyde reagents has been reported recently, 222 providing more possibilities for the design of stapled peptides.

Another frequent use of peptide cyclization is to stabilize various secondary structures like α-helixes and β-sheets, known as “mimicking secondary structures.” 2 , 223 Mimicking secondary structures employing strategies like cross-linking or hydrogen bond surrogates to replicate α-helices and β-sheets. 2 Key approaches for mimicking and stabilizing α-helices in peptides include lactam-based crosslinks, disulfide bonds, and biselectrophilic linkers. Lactam-based crosslinks form a lactam bridge by substituting lysine for the side chain of glutamic acid or aspartic acid, enhancing hydrogen bond formation and restricts conformational freedom of the peptide chain to mimic and stabilize alpha helical conformations. 224 Disulfide bonds can form covalent connections between peptide chains when N-terminal serine residues are replaced with homocysteine or cysteine. 225 Biselectrophilic linkers can react with two amino acid side chains on the peptide chains simultaneously to generate connections. 226 , 227 To stabilize β-sheets, peptides are modified by introducing D-amino acids, a successful example is the recently reported use of mirror-image phage display technology to select D-amino acid peptide ligands for aggregation-prone proteins that play a role in neurodegenerative diseases, thereby avoiding the accumulation of endogenous proteins such as amyloid beta peptide (Aβ), achieving therapeutic purposes. 228 As for β-sheet mimicking, there are also reports that have created β-sheet mimics via macrocyclization or amyloid. 229 , 230 In conclusion, mimicking secondary structures enhances stability and specificity, enabling a dynamic shift in peptide therapeutic design, allows creating structures that closely mimic protein-protein interfaces, demonstrating the potential of secondary structure mimicry.

D) Conjugation strategies

Conjugating peptides to larger molecules are also a method that has become quite popular in recent years, which not only increase lipophilicity, but the enhanced steric hindrance also prevents filtration of the conjugate through the kidneys and prolongs circulation time. Units commonly used to conjugate include lipids and polymers. Lipid conjugation strategy entails tying peptides to lipids such as glycerides, steroids, and fatty acids. 231 , 232 The principles behind this approach include forming stable ester or amide bonds, with fatty acids such as squalenoic acid and docosahexaenoic acid playing prominent roles. 233 , 234 The advantages offered by lipid conjugation include reduced toxicity and improved bioavailability. 235 An illustrative example involves the conjugation of the Poly (L-glutamic acid) (PGA), as the hydrophilic backbone, with the peptide antigen Ag and the molecular adjuvant imidazoquinoline (IMDQ) TLR7/8 agonist, respectively. The polyanionic properties of PGA were used to bind the electrostatic interaction of ionizable lipids condenses PGA-Ag and PGA-IMDQ into lipid nanoparticles. 236

Conjugation with polymers is another useful tactic to increase the stability, prolong the in vivo half-life, and lessen the immunogenicity of peptides, with PEGylation being a widely used technique. 237 This approach operates on the principles of extending half-life and mitigating immunogenicity, providing a shield against enzymatic degradation. 237 For instance, FDA-approved PEGylated proteins Krystexxa and PEGASYS have elevated the standard for stability and in vivo efficacy of peptide therapeutics. 238 Despite these gains, it has also been suggested that whereas conjugation shields targeting peptides from proteolysis to some extent, altering the peptide sequence to increase protease resistance can significantly increase homing and transport efficiency. 239

E) Terminal modifications

As exopeptidases typically break down peptide sequences at either the N- or C-terminus, it is possible to increase a peptide’s resistance to protease hydrolysis by modifying its terminus. N-acetylation, C-amidation, and fusion with albumin are the main concepts when it comes to terminal alterations and fusion tactics. 188 , 240 – 242 These modifications orchestrate an extended plasma half-life, amplifying the potential of peptide-based therapeutics. Exemplifying this, with site-specific albumin conjugation, a “clickable” non-natural amino acid named azide-l-phenylalanine (AzF) was added to three specific sites (V16, Y19, and F28) of the GLP-1 variant and then linked to HSA through a strain-promoted azide-alkyne cyclization reaction. The resulting three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) have serum half-lives comparable to HSA in vivo. 243

Conclusion and future directions

The future of structural modification of peptide drugs is poised to witness several exciting advancements. First, precision targeting is gaining prominence, with researchers designing peptides that exhibit high specificity for their intended targets, enabling precision targeting of disease-related proteins or receptors. 98 Additionally, we’re witnessing the emergence of multi-functional peptides that combine therapeutic effects with diagnostic capabilities or even serve as drug delivery vehicles. 244 Another promising trend involves stapled peptides, which stabilize peptide structures through covalent bonds, are expected to see further advancements to enhance peptide stability and bioavailability. 184 , 219 Besides, the exploration of novel peptidomimetics, synthetic molecules that mimic the properties of peptides, may help overcome limitations associated with natural peptides. 245 , 246

However, the field faces several research challenges that require innovative strategies to address. Improving the oral bioavailability of peptides, which often struggle with enzymatic degradation and poor absorption, remains a critical priority. 247 Prolonging the typically short half-lives of peptides without compromising their efficacy is another key challenge. 248 Overcoming immunogenicity, where some peptides can trigger unwanted immune responses, is also crucial. 195 As researchers explore more intricate peptide structures, the complexities of synthesis and characterization present additional hurdles. 184 , 249

To address these challenges, various technologies and strategies are being explored. Backbone modifications alter the peptide backbone to enhance stability and resistance to enzymatic degradation. Side chain modifications, achieved by substituting specific amino acids with modified analogs, can improve properties like solubility and binding affinity, might find applications in tailored therapeutics for diverse diseases. Conjugation with polymers extends half-life and improves pharmacokinetics, may see refinements for specific drug delivery needs. Cyclization, creating cyclic peptides, enhances stability and reduces susceptibility to proteases. Terminal modifications and fusion strategies are likely to be refined, offering extended half-lives for peptide therapeutics. Lastly, novel delivery systems, such as nanoparticles or liposomes, enhance tissue penetration and overall bioavailability. By leveraging these innovative strategies, the future of peptide drug development holds great promise in precision, multifunctionality, and overcoming existing limitations. 250

Advance of peptide-based therapeutics in diabetes

Obesity is a chronic progressive disease that affects nearly 760 million adults worldwide. Obesity not only affects human health and quality of life, but also increases the risk of T2DM, and cardiovascular disease. Diabetes is a chronic metabolic disease that is prevalent globally, with 537 million people already living with diabetes as of 2021, and T2DM accounts for approximately 90% of all people with diabetes, a number that is expected to continue to increase in the coming decades. 251 Diabetes imposes a huge burden on the health of individuals and society. In addition to obesity, complications such as diabetic cardiomyopathy, diabetic nephropathy, and diabetic foot can occur, increasing the rate of disability and death. 252

T2DM is primarily caused by insulin resistance and insufficient insulin secretion, and usually develops in adults, especially middle-aged and older adults. Weight management can be used to control the onset and progression of the disease in both T2DM and obese patients. Weight management is a lifestyle-based treatment that combines a personalized low-calorie diet, physical activity, and behavioral counseling. This intervention is able to reduce patient weight moderately (5%-10%) and control the onset of T2DM, but further weight loss is needed for effective control and most patients treated with weight management have difficulty adhering to it. 253 Although drugs such as exenatide and simethicone are now marketed for the treatment of diabetes, they are not yet sufficient, so the development of novel drugs remains important. 254 , 255

History of peptide-based therapeutics in diabetes

Insulin, the prototypical pharmaceutical agent for the treatment of diabetes, was initially derived and purified from the pancreatic tissue of a canine in 1921 and subsequently validated in a 12-year-old adolescent in 1922. In 1923, Eli Lilly and Company’s insulin (Insulin ® ) was launched on the market; in the same year, the Nobel Prize in Medicine and Physiology was awarded to the discoverers of insulin, such as Banting and MacLeod. However, the initial production method was not only complicated, costly and low-yielding, but also susceptible to immune reactions and viral infections. 256 With the advent of genetic engineering, researchers recombinantly obtained insulin in E. coli. Unlike extracted animal insulin, this type of insulin is attributed to human proteins, and the immune response is greatly controlled. 257 In 1982, Insulin human ® was approved by the FDA as the first recombinant therapeutic protein. 258 With the development of genetic and chemical engineering, the number of engineered insulins gradually increased and insulin modifications followed. 1996 saw the approval of Lispro ® (Humalog) as the first industrially engineered insulin. Detemir (Levemir ® ), which is a long-acting insulin, adds a fatty acid chain to the carboxyl terminus of the insulin β-chain. 259 Monnier et al. successfully prolonged the duration of insulin’s action by acylating insulin at LysB29, which allowed this peptide hormone to bind with endogenous serum proteins. In recent years, researchers have partially electrostatically mediated under the skin by introducing mutations at the C-terminal end of the β-chain leading to the aggregation of mutant insulins, allowing them to be gradually secreted into the bloodstream. 260 Many new insulin analogs have also been developed, such as the long-acting insulin analog Insulin glargine, which has a duration of action of up to 30 h, and the rapid-acting insulin analog insulin aspart, which has an immediate immediate onset of action after 10–15 min and peaks after 1–2 h (Table 6 ). 261 Table 6 Pharmacokinetic data of commercially available insulins Insulin preparations Onset of action Peak time Duration of action Prandial insulin Regular Insulin 30 min 1.5–2.5 h 5–8 h Insulin Aspart 10–15 min 60-90 min 4–5 h Insulin Lispro 10–15 min 1.0 h 4–5 h Basal insulin NPH 2.5–3.0 h 5–7 h 13–16 h PZI 3–4 h 8–10 h ≥ 20 h Insulin Glargine 1.1 h No peak ≥ 24 h Insulin Detemir 3-4 h No peak 24 h Insulin Degludec 1–2 h No peak 24 h

In 1923, Charles Kimball and John Murlin found and identified glucagon. In the 1980s, Joel Habener 262 described a new glucagon-related peptide encoded in the pre-glucagon cDNA of the pipefish. In the 1980s, Joel Habener described a new glucagon related peptide encoded in the pipefish pre-glucagon cDNA. Two glucagon related peptides were subsequently identified in rat, bovine, hamster and human glucagonogen. These two peptides are now referred to as GLP-1 and glucagon-like peptide-2 (GLP-2). GLP-2 is an enterotrophic hormone released by enteroendocrine cell (EEC) L cells, 263 and its receptor is mainly distributed in the digestive tract, exerting enteroprotective effects through different pathways GLP-2 acutely prevents endotoxin-related increased intestinal paracellular permeability in rats. Currently, the field of diabetes is dominated by the study of GLP-1. GLP-1 has a wide range of pharmacological and therapeutic uses. In addition to its ability to reduce gastric emptying, inhibit food intake, or control metabolism, the activation of the GLP-1 receptor induces a protective effect, the regulation of the hypothalamic-pituitary-adrenal axis, heart and lungs. It also reduces the production of inflammatory cytokines, chemokines, and the infiltration of immune cells in tissues, resulting in a broad range of neuroprotective and anti-inflammatory effects. GLP-1 interacts with its receptors to stimulate insulin secretion from pancreatic β-cells and inhibit glucagon release from pancreatic α-cells, increasing satiety and delaying gastric emptying in a glucose-dependent manner. Endogenous GLP-1 is degraded and rapidly inactivated by dipeptidyl peptidase-4 (DPP-4). To prolong the stimulation of GLP-1 receptors, GLP-1 RAs need to be synthesized to prevent their degradation.

GLP-1 RAs are emerging drugs for glycemic control and have been widely used in the treatment of T2DM in recent years. Currently, GLP-1 RAs are mainly categorized into peptide and non-peptide. Based on the similarity of their amino acid sequences, peptide agonists are mainly categorized into GLP-1 and derivatives and exendin-4 and derivatives. 252 In recent years, with the growing market size of the GLP-1 RA class of drugs, the U.S. glucose-lowering drug market has undergone a trend shift, evolving from insulin-based drugs as the star drugs before to GLP-1 drugs leading the way.

Since the FDA approved the first GLP-1 RA, Exenatide (Eli Lilly, Exenatide®), in 2005, six GLP-1 RAs have entered the clinic, including liraglutide (2010/2014/2016, Novo Nordisk A/S, Victoza ® /Saxenda ® /Xultophy ® ), lixisenatide (2016, Sanofi-Aventis, Lyxumia ® /Adlyxin ® /Soliqua ® ), albiglutide (2014, GSK Plc, Eperzan ® /Tanzeum ® ), dulaglutide (2014, Eli Lilly, Trulicity ® ), semaglutide (2017, Novo Nordisk A/S, Ozempic ® /Rybelsus ® ) and tirzepatide (2022/2023, Eli Lilly, Mounjaro ® /Zepbound ® ), in addition to efpeglenatide and taspoglutide which are in clinical studies. When injected, these GLP-1 RAs help the pancreas release the right amount of insulin when blood glucose is high, effectively lowering glycated hemoglobin and average blood glucose levels and improving fasting glucose.

As the first GLP-1 RA that can be used orally, semaglutide is able to effectively control blood glucose levels and achieve appetite reduction and weight loss by slowing down gastric emptying through brain regions that regulate appetite and food intake. 264 For patients with T2DM, the use of semaglutide has multiple implications. First, as a hypoglycemic drug, it can help patients effectively control their blood sugar levels and reduce the risk of stroke, heart attack, or death in patients with T2DM, as well as in patients with cardiovascular disease, and it is suitable for use in overweight/obese patients suffering from hyperglycemia, as well as, with a proper diet and exercise program. Secondly, semaglutide also has cardiovascular protective effects, 56 which is certainly an important therapeutic option for diabetic patients with comorbid cardiovascular disease or at high risk of cardiovascular disease. In addition, Novo Nordisk has made three modifications to semaglutide: 1. alpha-aminoisobutyric acid has been used to replace alanine at position 8. 2. a C18 lipoic acid side chain has been linked to lysine at position 26, with glutamic acid as the linker. 3. arginine has been used to replace lysine at position 34. The above three modifications enable the ultra-long-lasting characteristics of semaglutide, which needs to be taken orally only once a week, which greatly improves the convenience of dosing and patient compliance.

In addition to the hypoglycemic effect, the weight loss effect of semaglutide has also attracted much attention. By slowing down gastric emptying, increasing satiety and acting on the hypothalamus to suppress appetite, semaglutide is able to effectively reduce dietary intake, thus achieving weight loss. Studies have shown that semaglutide can reduce body weight by 15 to 20%, which is far more effective than previously approved weight loss medications. For obese type 2 diabetic patients, semaglutide can not only help them control blood glucose, but also effectively reduce weight, which is of great significance to improve the metabolic status of diabetic patients.

Efpeglenatide, currently in development, is a long-acting GLP-1RA used to control blood glucose levels in patients with T2DM. Efpeglenatide consists of a modified exendin molecule and is coupled to a fragment of human immunoglobulin 4 by a special technology called long-acting peptide. This special coupling technology allows for a more flexible dosing frequency of efpeglenatide. 265 Epernatide is also less desensitizing than other therapeutic agents, which means that epernatide has a longer-lasting therapeutic effect. However, eperinatide is still in the developmental stage, and its other related properties and characterization need to be developed in subsequent studies.

Similar to GLP-1, GIP is an intestinally secreted peptide that promotes insulin biosynthesis and islet β-cell differentiation and reduces apoptosis. Clinical trials have shown that the GIP/GLP-1 dual-targeting combination has shown effective weight loss and glucose-lowering effects. Based on these two important targets, Lilly developed tirzepatide (Zepbound ® ), the first marketed dual-target agonist (GIP/GLP-1) obesity treatment injection, which provides better weight control than semaglutide and dulaglutide (Fig. 8b ). 266 The drug has previously been approved as an adjunctive therapy to diet and exercise to improve glycemic control in T2DM. 267 , 268 Tirzepatide consists of 39 amino acids, 37 of which are naturally occurring (or coded) and two are non-naturally occurring. Non-coding amino isobutyric acid residues at positions 2 and 13. Besides, it is amidated at the C-terminus, which binds the C 20 lipoic acid portion through a spacer region attached to Lys20. 269 This side-chain structure has been cleverly designed to not only improve the stability and bioavailability of the molecule, but also to enhance its affinity for the target. For dual activity, it incorporates amino acid residues primarily from GLP-1 and GIP and uses some unique amino-acid residues. Studies have shown that tirzepatide improves pancreatic β-cell function and insulin sensitivity, and compared to traditional GLP-1 RA, these drugs have a longer duration of action, allowing for a reduction in the frequency of weekly dosing. 270 Fig. 8 Sales and structures of the top five selling GLP-1 agonists. a The total income from sales of the top five selling GLP-1 agonists. b The protein composition, linkage order and characteristic structure of the top five selling GLP-1 agonists

Meanwhile, the research and development of triple-target agonists is also a current hot issue. It has been found that retatrutide, a 39 amino acid peptide, can resist cleavage by dipeptidyl peptidase IV, which is responsible for breaking down GLP-1 and GIP, 271 and it also stimulates GLP-1, GIP and glucagon receptors, which is potentially useful for treating obesity and T2DM. However, studies have shown that retatrutide can increase heart rate by 6.7 beats per minute, 272 which may be harmful and counteract some of the benefits of weight loss. Retatrutide is currently in the developmental testing phase and more detailed data is pending subsequent studies, but the availability of retatrutide still offers a new direction in the treatment of T2DM.

In addition, there are some potential drugs that may also have an effective effect on diabetes. C-peptide, as a bioactive peptide, can reflect the indicators of pancreatic β-cell function as well as bind to signaling molecules on the surface of the cell membrane and activate its own signaling pathway, exerting antioxidant, anti-apoptotic, and anti-inflammatory effects, or regulating cellular transcription through internalization. It has been found that the bioactivity of C-peptide can be used to prevent and treat the complications of diabetes and thus influence the comprehensive treatment of T2DM. Currently, the relationship between C-peptide and chronic complications of diabetes is complex and clinical trials have been unsatisfactory, requiring control of baseline C-peptide levels. Efpeglenatide, currently in development, is a long-acting GLP-1 RA for controlling blood glucose levels in patients with T2DM. 273 Efpeglenatide consists of a modified exendin molecule and is coupled to a fragment of human immunoglobulin 4 by a special technology called long-acting peptide This special coupling technology allows for a more flexible dosing frequency of efpeglenatide. At the same time, eptifibatide is less desensitizing than other therapeutic agents, which means that eptifibatide has a longer-lasting therapeutic effect.

Progress of GLP-1 receptor agonist repositioning studies

In recent years, GLP-1 has made many important advances in a number of research areas, including the cardiovascular system, central nervous system, obesity and metabolic syndrome, insulin secretion, muscle and liver (Fig. 9 ). Studies have found that GLP-1 RAs have multiple beneficial effects in the cardiovascular system, including improving cardiovascular function and inhibiting the development and rupture of atherosclerotic plaques, and thus GLP-1 RAs may have cardiovascular protective potential, slightly reducing the risk of death due to cardiovascular disease and any cause, and slightly reducing the risk of stroke compared to placebo. Recent studies have shown 274 that GLP-1 may also regulate appetite and energy balance by affecting neuronal activity and synaptic transmission, which is critical for appetite and weight regulation. In addition, GLP-1 plays an important role in the pathogenesis of obesity and metabolic syndrome. It has been found that obese patients often have GLP-1 resistance, resulting in reduced GLP-1 bioactivity. Therefore, researchers are exploring ways to increase GLP-1 activity to improve the treatment of obesity and metabolic syndrome. Some scholars’ research shows that Liraglutide can reduce the occurrence of neuroinflammation to a certain extent while reducing Aβ plaques, and the above two are important causes of Alzheimer’s disease (AD), so GLP-1 RAs have great potential in the treatment of AD. 275 Because Liraglutide has certain anti-inflammatory effect, can reduce the occurrence of neuroinflammation, some scholars believe that it will also play an irreplaceable role in the treatment of Parkinson’s disease. Some experimental studies have shown that Liraglutide can also activate SIRT1 to a certain extent, which is an important factor in regulating muscle cell metabolism, and can prevent muscle atrophy, so GLP-1 RAs provides new ideas for the treatment of muscular dystrophy and other diseases. In addition, Liraglutide has been verified to reduce the possibility of hepatic steatosis by participating in autophagy-lysosomes. The use of semaglutide prior to total hip arthroplasty has been shown to reduce postoperative prosthetic joint infections and readmissions. All of the above suggests that there is great potential for GLP-1 RAs in the treatment of a wide range of conditions. Fig. 9 Prospect for peptide drugs targeting GLP-1 agonists in six other tissues and organs. Figure 9 was created with biorender.com

Advance of peptide-based therapeutics in cancer

Cancer is one of the primary factors affecting human health and leading to mortality. According to World Health Organization statistics, nearly 10 million deaths (almost one in six) are caused by cancer in 2020. 276 Despite the breakthroughs in immunotherapy in recent years, the current clinical treatment of tumors is still dominated by chemotherapy, surgery and radiotherap. In this regard, surgical procedures are prone to trauma and bleeding, as well as posing risks of infection and weakened immunity. 277 Radiotherapy is prone to a variety of complications, as well as high costs and long treatment times. 278 Chemotherapy has significant side effects and fails to differentiate between normal and tumor cell. In addition, chemotherapy often leads to the development of drug resistance and is prone to relapse 279 ; Although immunotherapy has significantly fewer side effects than chemotherapy, 280 , 281 the effectiveness of treatment varies with each individual, and it also has the potential to trigger autoimmune myocarditis 282 or induce cytokine storms. 283 Therefore, new treatments or anti-tumor drugs are urgently needed to be researched and developed to meet the various needs. Anti-cancer peptides (ACPs) have gradually received attention from researchers in the field of tumor therapy because of their high specificity and safety advantages.

ACPs are a class of anti-tumor active peptides within antimicrobial peptides (AMPs), typically possessing a positive charge, high hydrophobicity, and strong penetrability. 284 Then, it can be used as a hormone and inhibitor or as a peptide vaccine to activate anti-tumor immune responses. 285 , 286 Besides, these peptides can be used for imaging, cancer diagnosis, and targeted drug delivery, even some specific peptides can be engineered to attack cancer cells and prevent tumors from worsening. 287 Based on the types, quantities, and structures of amino acids, ACPs can be classified into four categories: α-helical, β-pleated sheets, random coil and loop structures. 288 From the perspective of source, it mainly includes natural peptides, peptides obtained from combinatorial libraries (more details in section “Display library technology”), as well as synthetic or modified peptides. 284 It has complex mechanisms of action, including inhibiting tumor angiogenesis, disrupting cell membranes, interfering with metabolism, targeting cytoplasmic components and mediating immune cell regulation, etc. An overview of the research on peptides in the direction of anti-tumor is presented in Fig. 10 . Fig. 10 Models of anti-tumor mechanisms of ACPs. The direct mechanism of ACPs is performed through interacting with negatively charged membranes, resulting in increased membrane permeability, cell membrane lysis, or release of intracellular contents, which ultimately leads to cell death. There are three main models of membrane pore formation, namely barrel stave model, toroidal pore model, carpet model. After the antitumor-peptides enter the phospholipid membrane, its hydrophobic region binds to the inner hydrophobic region of the phospholipid bilayer, and the hydrophilic region is exposed to the outside. Another mechanism is that the ACPs penetrates into the cytoplasm and interacts with intracellular substances, such as inhibiting DNA, RNA and protein synthesis, causing autophagy, promoting calcium ion in-flow, causing cleavage of cellular organelles, and disrupting cellular structure by the outflow of contents

Peptides for anti-cancer

A) Natural anti-cancer peptides

Natural ACPs are widely found in animals, plants and microorganisms. For example, oncolytic peptides (e.g., anoplin) can selectively cleave tumor cell membranes and remain effective against drug-resistant tumors. 289 Some studies have also proved that oncolytic peptides have potential role in activating anti-tumor immunity. The first drug named “oncolytic peptide”, LTX-315 (Ruxotemitide, Oncopore), is currently in phase II clinical trials and can induce complete ablation of a variety of tumors. 290 , 291 Wang KR et al. isolated a cationic ACPs, Polybia-MPI, which was originally isolated from the venom of the social wasp Polybia paulista. Its primary sequence is IDWKKLLDAAKQIL-NH2. 292 , 293 It targets non-polar lipid cell membranes, forming ion-permeable channels and leading to depolarization, irreversible cytolysis, and eventual cell death. The results showed that polybia-MPI exhibit antitumor activity by disrupting the cell membrane of cells, while it has lower cytotoxicity to erythrocyte and normal fibroblast. 292 It is also unaffected by conventional multi-drug resistant mechanisms and has the potential to be used as a chemotherapeutic agent against multi-drug resistant tumors. 294 In addition, anti-tumor peptides, such as Apicidin(cyclo(N-O-methyl-L-tryptophanyl-isoleucinyl-D-pipecolinyl-L-2-amino-8-oxodecanoyl)), can be obtained from fungal metabolites. It is a selective inhibitor of histone deacetylase (HDAC) and has been shown to have potent anti-angiogenic activity and reduce the level of hypoxia inducible factor-1α (HIF-1α) in human and mouse tumor cell lines. 295 , 296 In the HCT-116 xenograft tumor model of human colon cancer, Apicidin inhibited tumor growth. Moreover, apicidin also showed anti-tumor activity in Ishikawa cell xenograft tumor model, which could inhibit the proliferation of eight tumor cell lines, including HeLa, MCF-7 and HBL-100. 297

B) Synthesized or modified anti-cancer peptides

Natural peptides as potential drug candidates have the advantages of high selectivity, biocompatibility, diversity of targets of action, and low toxicity, however, natural peptides also have some disadvantages. The instability of some natural peptides can lead to their susceptibility to degradation by gastric acids and enzymes, which reduces their effectiveness in oral drug delivery. In addition, peptides derived from natural sources usually have high production costs, limiting their large-scale application. In order to overcome the limitations of natural peptides, the development of peptide synthesis and modification techniques has become crucial. Synthetic technologies can produce peptides with specific sequences and structures, improving their stability and biological activity. Additionally, modification techniques can change the physical and chemical properties of peptides and enhance their drug compatibility, bioavailability and targetability. 298 The development of peptide synthesis and modification technologies can further expand the application of peptides as drugs, improve their therapeutic efficacy and reduce their side effects. Here we described typical and some new synthetic peptides. For more details on peptide modification techniques are described in section “Enhancing peptide stability and bioavailability through structural modifications”, where we have summarized them in more detail.

In the 1950s, since du Vigneaud et al. 11 synthesized the first peptide, Pitocin® (oxytocin), the technology of peptide synthesis has developed rapidly. Peptide synthesis techniques include two categories: biosynthesis and chemical synthesis. Furthermore, Biosynthesis methods can be divided into natural extraction, enzymatic, fermentation and genetic recombination methods, etc. The chemical synthesis of peptides is further divided into SPPS 299 and Liquid Phase Peptide Synthesis (LPPS). 300 Both of them play important roles in the field of peptide synthesis.

As far as biosynthesis is concerned, the desired peptides are mainly obtained by microbial fermentation, enzyme catalysis and genetic recombination, etc. For example, the synthesis of formadicin, ramoplanin, vancomycin, and teicoplanin. 301 Besides, the synthesis of the bis-intercalators family is highly dependent on biosynthetic methods. Bis-intercalators family are a class of C 2 -symmetric cyclic non-ribosomal peptides produced by actinomycetes, which can be inserted into DNA molecules through two unique chromophores in their structures, hence possessing good biological activities such as antimicrobial and antitumor activities. The complex molecular structure of the double-embedded family of non-ribosomal peptides makes chemical synthesis very challenging, while microbial fermentation is the main method for the production of this family of compounds. Thiocoraline, 302 Triostin A, 303 and Echinomycin 304 are members of the bis-intercalators family, their synthesis is often via biosynthetic methods. Their key core skeletons, such as 3-hydroxyquinaldic acid, (3HQA), quinoxaline-2-carboxylic acid, (QXC) and 6-methoxy-3-hydroxyquinaldic acid, are synthesized in the presence of a range of enzymes (e.g. thioesterase) are synthesized. Finally, a series of fragments are assembled stepwise to obtain the corresponding antitumor peptides. 305

On the other hand, with respect to chemical synthesis methods. LPPS is mainly composed of two strategies: stepwise synthesis and fragment combination. The advantages of LPPS include low cost, a wide choice of protecting groups, easy to scale up the synthesis, suitable for the synthesis of short peptides, and convenient purification. 300 SPPS was proposed by Merrifield 299 in 1963 and has been greatly developed to date. According to the different α-amino protecting groups, it can be divided into tert-butoxy-carbony (Boc) method and 9-fluorenyl-methoxycarbonyl (Fmoc) method. 38 , 306 Compared with liquid-phase synthesis, solid-phase synthesis is convenient to operate, easy to realize automated processing, higher product yield and purity, which greatly promotes the development of peptide drugs. 307 Nowadays, the synergies between solid-phase and liquid-phase synthesis methods play an important role in the field of peptide synthesis. In addition, as auxiliary technologies, microwave-assisted synthesis as well as advances in microchannel flow technology have made it possible to precisely control the reaction time (<1 s) and temperature, which greatly enhances the efficiency. 38 , 308 , 309 For example, the synthesis of feglymycin using a linear method of microfluidic amide bond formation has enabled the preparation of biologically active oligopeptides with highly racemized amino acids, which are attractive drug candidates. 310

Reniochalistatin E, the only tryptophan-containing cyclo-octapeptide in the reniochalistatins family. To date, it is the only peptide with antitumor activity (including RPMI-8226, MGC-803, HL-60, HepG2, and HeLa) among all the members of the reniochalistatins family, and it is particularly cytotoxic to myeloma RPMI-8226 and gastric MGC-803. 311 , 312 It uses 2-chlorotriphenyl chloride (CTC) resin as the carrier and HCTU/DIPEA as the condensation system to synthesize the straight-chain peptide by Fmoc solid-phase synthesis and liquid-phase cyclization to obtain the cyclic peptide crude product. Then it was purified through preparative liquid chromatograph. Next, the product was characterized by HPLC, MS and NMR. Finally, the purity of the target product as well as the overall yield was significantly higher than that of the peptide obtained from this reniochalina stalagmitis. 313 This method is simple and easy to operate, applicable to the synthesis of the series of cyclic peptides.

HYD-PEP06 is a peptide compound obtained via Solid-Phase synthesis by Yang et al. 314 It is an RGD-modified endostatin-derived synthetic peptide consisting of 30 amino acids. Its N-terminal RGDRGD fragment can specifically bind to different integrins in endothelial cells, which has been shown to have anti-tumor effects in colorectal cancer, oral squamous cell carcinoma and hepatocellular carcinoma (HCC). 315 , 316 Based on the “one drug and two targets” design, Yang et al. selected the anti-tumor active fragment of endostatin and carried out structural modification and optimization on this basis, so that it could not only inhibit vascular activity, but also further have de-integrin effect. The mechanism of HYD-PEP06 is to block PI3K/AKT to inhibit the epithelial-mesenchymal transformation of liver cancer cells. Moreover, it also can inhibit the glomus formation and migration of liver cancer tumor stem cells by blocking the Wnt/β-catenin signaling pathway, so as to delay the development of liver cancer. Research has shown that HYD-PEP06 can inhibit the growth of subcutaneous graft tumor remnants of hepatocellular carcinoma in nude mice and has significant therapeutic effects on lung metastasis of hepatocellular carcinoma. 314 It is a promising drug for the treatment of hepatocellular carcinoma and colorectal cancer by regulating the action of tiny nucleotides, ion channels and tumor stem cells, thus comprehensively inhibiting tumor recurrence and metastasis. Currently, the drug has completed undergoing clinical phase I trials (CTR20213196), and is actively undergoing clinical phase II trials (CTR20220769).

Furthermore, there are a number of globally approved drugs that utilize chemical synthesis techniques, including Sandostatin ® (octreotide), Velcade ® (bortezomib), Aphexda ® (motixafortide).

Octreotide (Sandostatin ® ) is a typical octapeptide derivative synthesized using the Fmoc-SPPS method. The synthesis of octreotide acetate by solid-phase peptide synthesis and the adoption of the trans-salt process has the characteristics of simple operation, easy to operate, higher yield, etc., which are suitable for industrialized production. 317 It is pharmacologically mimicking natural growth hormone. However, it is more potent than the natural hormone. 318 Octreotide acts on the somatostatin receptors and causes vascular smooth muscle contraction by inhibiting the coupling of G proteins to phospholipase C. Like somatostatin, it induces an increase in calcium entry through L-type calcium channels, which leads to an increase in calcium-induced calcium release from the sarcoplasmic reticulum in smooth muscle cells through calcium-induced calcium release channels of the ryanodine receptor, then, it initiates the contractile cycle through activation of myosin light-chain kinase via interaction with calcium-calmodulin. 319 Besides, octreotide can directly inhibit tumor angiogenesis by down-regulating growth hormone (GH) release. 318 , 320 And its two formats, injection and slow-release microspheres, were approved by the FDA for the treatment of carcinoid tumors, vasoactive intestinal peptide tumors, in 1988 and 1998, respectively. 321 Additionally, octreotide is a classic therapeutic peptide that is also used in chemotherapy-associated refractory or intractable diarrhea, graft-versus-host disease, and HIV-associated diarrhea due to cryptosporidiosis, but is not approved by the FDA. 322 Similarly, there are drugs such as lanreotide and pasireotide that exert the same effect. Furthermore, octreotide has been successfully used in imaging (neuroendocrine, endocrine, breast, small cell lung and prostate cancers) and more recently in targeted radiation therapy. 323 It is one of the more prominent examples.

Bortezomib (Velcade ® ), a reversible inhibitor of the 26S proteasome, was obtained by chemical synthesis. It can be synthesized by convergent approach, and the use of TBTU (a condensation reagent, O-Benzotriazol-1-yl-N,N,N’,N’-tetramethyluronium tetrafluoroborate) inhibits the racemization during fragment condensation. It was approved by the FDA as a borate peptide for the treatment of multiple myeloma in 2003. Then Approved for mantle cell lymphoma in 2006. This drug exerts its antitumor effects mainly by inhibiting key substances in nuclear factor κB (NF-κB) pathway involved in cell proliferation, apoptosis, and angiogenesis. 324 However, it is associated with hematotoxicity and peripheral neuropathy, as well as exhibiting poor permeability and pharmacokinetic parameters in solid tumors. Additionally, its chemical stability and bioavailability are low. Recent studies have demonstrated that nanoparticle delivery can overcome these limitations, offering a solution to circumvent the challenges encountered by conventional cancer chemotherapy drug administration. 325

Motixafortide (Aphexda ® ) is a synthetic cyclic peptide approved by the FDA in September 2023. 326 It is utilized in combination with filgrastim (granulocyte colony-stimulating factor G-CSF) to facilitate the mobilization of hematopoietic stem cells into the peripheral blood for subsequent collection and autologous transplantation in patients diagnosed with multiple myeloma. Notably, motixafortide is the first innovative drug in nearly a decade to be approved by the FDA in the field of stem cell mobilization in multiple myeloma. It was shown that motixafortide blocks the interaction between CXCL12 and CXCR4 by binding to CXCR4 on hematopoietic stem cells (HSCs) and having a long receptor occupancy (>48 h). 206 , 327 Peripheral blood and stored HSCs collected by apheresis were injected back into the patient (autologous transplantation) or into the recipient patient (allogeneic transplantation) to repopulate the bone marrow. Furthermore, motixafortide has been demonstrated to effect “cold” tumors in multiple modes of action, such as immune cell migration, tumor infiltration by immune effector T cells, reduction of immunosuppressive cells (e.g., Myeloid-derived suppressor cells, MDSCs) in the tumor microenvironment, etc. which can turn “cold” tumors (e.g., pancreatic cancer) “hot” (i.e., sensitizing them to immune checkpoint inhibitors and chemotherapy). 206 , 328 , 329 And then, in a Phase II clinical trial, motixafortide in combination with cemiplimab and gemcitabine showed very significant results in the treatment of patients with pancreatic cancer. 206 , 326

In the case of chemically modified peptides, for example, Polyethylene glycol (PEG) modification, Amino acid substitution modification and Cyclization modification and, etc. More details on the content of modified peptides are in section “Enhancing peptide stability and bioavailability through structural modifications”. Here we won’t describe it too much.

The occurrence and development of human tumors are related to the inhibition and intracellular degradation of p53 by negative regulatory proteins murine double minute 2 (MDM2) and murine double minute 4 (MDM4 or MDMX) of tumor suppressor p53. Therefore, antagonizing MDM2 and MDMX to activate and stabilize p53 is an important strategy for anti-tumor drug design. 330 The peptide PMI (TSFAEYWNLLSP), which inhibits p53-MDM2 interaction with high solubility and specificity, was synthesized by phage display technology. 331 , 332 However, the side chains of multiple residues of PMI are prone to interact with each other. Based on this, Lu et.al. screened and designed a peptide PMI-M3 (LTFLEYWAQLMQ) with low affinity for MDM2 and MDMX in pmol/L level through systematic mutation analysis and free energy addition principle. 175 In addition, the researchers also obtained modified peptides of PMI-2K (KTSFAEYWNLLSPK) and M3-2K (KLTFLEYWAQLMQK) by adding lysine residues at both ends of PMI and PMI-M3 to improve their cellular uptake. Moreover, M3-2K can significantly improve the anti-tumor activity of p53-dependent in vitro and in vivo, and this p53-MDM2/MDMX interaction is expected to be further developed as a peptide inhibitor.

Peptides used in tumor diagnosis

Peptides can not only be used as drugs, but also used as molecular probe tools for molecular diagnosis and imaging of tumors. Peptides scintigraphy and peptide receptor radiotherapy have been developed based on the fact that tumor cells express one of the five growth inhibitory receptor subtypes. Currently, radioactive elements such as indium 111 (In), yttrium 90 (Y), gallium 68 (Ga), and technetium 99 m (Tc) can selectively bind to different somatostatin analogs via chelating groups. 333 Here we focus on peptides developed in recent years for use in imaging and diagnostics.

In 2016, [ 68 Ga]Ga-DOTA-TOC was approved by the EMA for the specific imaging of tumor cells expressing somatostatin receptors (SSTRs), a radiopharmaceutical that combines the radionuclide 68 Ga with the somatostatin analog DOTA-TOC to function. Then, the FDA approved [ 68 Ga]Ga-DOTA-TOC in 2019 as the first 68 Ga radiopharmaceutical in the U.S. to use positron emission tomography (PET) to image the somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors. This radioactive probe will help locate tumors in adults and children with a rare disease, somatostatin receptor-positive neu-endocrine tumors (NETs). 334

Similarly, Illuccix ® , also called gallium ( 68 Ga) gozetotide or gallium ( 68 Ga) PSMA-11 was approved by the FDA in 2020 for PET imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, in which this radiopharmaceutical combines the radionuclide 68 Ga with a mimetic peptide, Glu-NH-CO-NH-Lys(Ahx)-HBED-CC, which allows for the PSMA-expressing tumor cells for specific imaging. This targeting approach can also be used to develop treatment plans and potentially to assess treatment response. Notably, it is the first drug to use radioactive 68 Ga for PET imaging of PSMA-positive prostate cancer. 335

In addition, Pluvicto ® (lutetium Lu 177 vipivotide tetraxetan, 177 Lu-PSMA-617) is also available for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC), who have received prior androgen receptor (AR) inhibitor and paclitaxel-based chemotherapy, which was approved by the FDA in March 2022. 92 Similarly, Posluma ® (flotufolastat F-18), a high-affinity PSMA-targeted radio-diagnostic reagent based on a novel radio-hybridization technology, was approved by the FDA in May 2023 for testing in males with suspected metastatic prostate cancer for PET (Positron Emission Tomography) of PSMA prostate-specific membrane antigen (PSMA)-positive lesions. 336

Generally, possessing the advantage of peptides in nature, anti-tumor peptides can inhibit the proliferation, migration and invasion of tumor cells and promote the apoptosis of tumor cells by preventing protein interaction, regulating the conformation of biomolecules, competing for receptor binding and destroying the cell membrane. In addition, anti-tumor peptides are able to be used as molecular probe tools for tumor molecular diagnosis and imaging in the field of tumor drug therapy. At the same time, peptides from different sources can be modified to make them have longer half-life, stronger resistance to enzymatic hydrolysis, relatively complete pharmacokinetic properties. With the in-depth understanding of tumor pathology and the development of new drug discovery technology, it is believed that more anti-tumor peptide drugs will be developed in the future.

Advance of peptide-based therapeutics in cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in the world, accounting for about 50% of all deaths. 337 The World Heart Report, launched at the 2023 World Heart Summit, shows that CVD deaths jumped globally from 12.1 million in 1990 to 20.5 million in 2021, with four in five of those deaths occurring in low and middle-income countries. 338 Diabetes mellitus, obesity, hypertension, hyperlipidemia, and other factors are high risk factors for cardiovascular disease, which manifests itself clinically as impaired cardiac function due to myocardial hypertrophy and fibrosis, and ultimately, death resulting from heart failure. A variety of ways have been used in preclinical studies for the treatment of cardiovascular disease, including small molecule drugs, protein drugs, and gene therapy to address the pathologic process. 339 – 343 Peptides, due to their advantages, have become important therapeutic agents for cardiovascular diseases focusing on the symptoms of hypertension, vascular function and coronary artery disease, and acute coronary syndromes (ACS). Here, we briefly presented the overview of peptides in cardiovascular diseases.

Peptide drugs acting on G protein-coupled receptors

GLP-1 is an incretin secreting hormone secreted by intestinal L cells. GLP-1 receptor is a class B G protein-coupled receptor, which plays an important role in glucose homeostasis and the treatment of T2DM. 344 GLP-1 exerts its effects through GLP-1 receptor binding. Studies have found that GLP-1 receptor is not only expressed in islet β cells, but also widely distributed in brain, lung, gastrointestinal tract, kidney, liver, heart and other organs in the body. 252 , 345 Therefore, GLP-1 RAs may have effects on multiple organs, and the development of such drugs opens new ideas for the treatment of various clinical diseases. The first GLP-1 RAs is exenatide, which was approved by the FDA for the treatment of T2DM in 2005. Studies have shown that GLP-1 RAs is not only effective in glycemic control, but also beneficial in the prevention of cardiovascular disease and weight loss similar to sodium-glucose transporter 2 (SGLT2) inhibitors. 346 For example, liraglutide, dulaglutide and semaglutide can significantly reduce the incidence of major cardiovascular events (MACE) in patients with T2DM. In addition, the study showed that the risk of MACE in T2DM patients with a history of cardiovascular disease was significantly reduced by 14%, while the risk of MACE in patients without a history of cardiovascular disease was significantly reduced by 6%. 345 , 347 In addition, the use of GLP-1 RAs in nondiabetic patients has focused on a modest improvement in left ventricular function after 7 days of acute treatment with the GLP-1 RA in patients with ST-segment elevation myocardial infarction (STEMI). 348 , 349 Similar results were seen in patients without STEMI, independent of diabetes status. This suggests that GLP-1 RAs has some preventive effect on cardiovascular events in nondiabetic populations, but more study data are needed to support this. Although the peptide GLP-1 RAs is not FDA-approved for the treatment of cardiovascular disease, the potential therapeutic pleiotropic effects of the peptide GLP-1 RAs in patients with cardiovascular disease may extend beyond the treatment of diabetes in the future. 350

Human urotensin-II (UII) is the strongest vasoconstrictor found in mammals. 351 and it acts through the activation of the UII receptor (UT), the orphan G protein-coupled receptor (GPR14), collectively referred to as the UII/UT system. 352 Urantide is a peptide UT antagonist derived from Urotensin II(UII). 353 Urantide contains a core peptide consisting of six amino acid residues (Cys-Phe-Trp-Lys-Tyr-Cys), which has certain biological activity. Therefore, urantide has a high affinity with the UTs of human, mouse, monkey and other animals. Studies have shown that urantide can reduce the content of oxygen free radicals and anti-lipid peroxidation in myocardial tissue by activating PI3K /Akt and PKC signal transduction pathways, further regulate the expression of Bcl-2-associated X (Bax) and B-cell lymphoma 2 (Bcl-2) proteins, and inhibit the apoptosis of myocardial cells in rats with myocardial ischemia/reperfusion. 198 Attenuating cardiotoxicity induced by doxorubicin and protecting primary cardiomyocytes depended on the down-regulation of p38 in the MAPK pathway. 354 The protective effect of urantide on DOX-induced myocardial injury was more obvious. In studies where allantoin was administered to rats with atherosclerosis, it was found that allantoin reduced myocardial injury and lowered, serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels by blocking the UII/UT system and regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Urantide also reduced the levels of UII and its receptor, p38, p-extracellular signal-regulated kinase (ERK) and p-c-Jun N-terminal kinase (JNK) in myocardial tissue to protect cardiovascular function. 354 , 355 At present, the research of urantide in cardiovascular diseases is still in the stage of animal experiments.

Peptide drugs acting on natriuretic peptide receptors

Natriuretic peptides (NPs) family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). 356 play an important role in the prevention of plasma volume expansion and hypertension. 357 Natriuretic peptide regulates cardiovascular homeostasis mainly through three membrane receptors: natriuretic peptide receptor A (NPR-A) and natriuretic peptide receptor B (NPR-B) are guanylyl cyclase-coupled receptors, and natriuretic peptide receptor C (NPR-C) is a non-guanylyl cyclase-receptor on the cell surface. 358 NPs mainly act through NPR-A and/or NPR-B receptors, while NPR-C is mainly used to remove NPs. 359 The cardiovascular effects of natriuretic peptides include a reduction in peripheral vascular resistance and cardiac preload. 360 , 361 Nesiritide, a recombinant human brain natriuretic peptide (rh-BNP) that mimics brain natriuretic peptide (BNP) action, plays a role in patients with decompensated heart failure. Clinical studies with intravenous injections have shown that, Nesiritide has a potent, dose-related vasodilator effect that is rapid and long-lasting. It was approved by the FDA in 2001 for the treatment of acute decompensated heart failure in patients at rest or with mild dyspnea. 362 , 363 However, nesiritide is not widely used due to, which has side effects of headache and decreased blood pressure, low specificity and safety, now withdrawn from the market. 362 , 364

Carperitide, a cyclic, recombinant α-human atrial natriuretic peptide (hANP), was approved by the PMDA in 1995 for the treatment of acute congestive heart failure (ADHF). 365 , 366 ANP often induces a biological response by binding to guanylate cyclase-coupled receptor NPR-A. The use of carperitide in patients with ADHF can reduce central filling pressure and plasma aldosterone concentration, increase cardiac output, diuresis, and improve hemodynamics in the acute phase of ADHF. 367 Hypotension was considered to be the most common adverse effect of caperitide, followed by renal dysfunction, and the increased in-hospital mortality in ADHF patients was significantly associated with the use of caperitide. However, a low dose (0.025-0.050 μg/kg/min, 0.0125 μg/kg/min in some cases) of continuous intravenous infusion of carperitide can reduce side effects and in-hospital mortality, but this report still needs to be confirmed by a large number of samples and multi-center trials. 368 In addition, carperitide can also increase coronary blood flow (CBF), reduce myocardial contraction and metabolic dysfunction, and limit infarct size. Among them, nitric oxide (NO) plays an important role in carperitide-induced ischemic heart vasodilatation and cardioprotection. 369

Peptide drugs acting on angiotensin-converting enzyme (ACE)

Hypertension is a common chronic cardiovascular disease characterized by persistently elevated arterial blood pressure. It is a major risk factor for cardiovascular diseases such as atherosclerosis, coronary heart disease, stroke and myocardial infarction, besides, it is also a major cause of premature death worldwide. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, β-adrenoceptor blockers and diuretics are commonly used antihypertensive drugs in the world. 370 These antihypertensive drugs have good antihypertensive effects, but there are also many side effects. For example, some drugs that normally lower blood pressure may abnormally raise blood pressure, or increase blood pressure after stopping the drug, and cause symptoms such as dry cough, rash, edema, and acute renal impairment. 371 , 372 Among the active peptides that have antihypertensive effects, most of them achieve their antihypertensive effects by inhibiting the activity of ACE. Active peptides with antihypertensive effects are similar to other peptide drugs in that they exert their therapeutic effects (lowering blood pressure) without any side effects on the body. Ace-inhibiting peptides are derived from a wide range of animal, plant and Marine organisms through the hydrolysis of hydrolases (e.g., pepsin, chymotrypsin and trypsin) and microbial enzymes (e.g., alkaline protease, thermolysin, conditase and proteinase K). 373

LKPNM, a peptide derived from Katsuobushi, is an ACE inhibitor with antihypertensive activity, it has been used as a pharmaceutical ingredient in antihypertensive capsules. 374 , 375 ACE-inhibiting peptides have also been identified from other species. For example, ACE-inhibiting peptides have been identified from other species, such as four peptide sequences (Gly-Gly-Pro-Ala-Gly-Pro-Ala-Val, Gly-Pro-Val-Ala, Pro-Pro, and Gly-Phe) isolated and extracted from salmon gelatinase hydrolysate (SC-1), which possess ACE and dipeptidyl peptidase IV (DPP-IV) inhibitory activity as well as oxygen radical uptake capacity. The peptides showed strong antihypertensive effects in a rat model of spontaneous hypertension, suggesting that the peptides could be used as pharmaceutical ingredients for the treatment of hypertension and related diseases. 376 The results indicate that this polypeptide may be used as a drug preparation for the treatment of hypertension and related diseases.

Novel ACE-inhibiting peptides, VVLASLK, LTLK, LEPWR, ELPPK and LPTEK, were screened, identified and synthesized from cutlass, among which peptide LEPWR exhibited the best ACE-inhibiting ability. The antihypertensive effect of the ultrafiltration fraction was confirmed by using a spontaneously hypertensive rat (SHR) model. LEPWR antagonize ACE in a mixed competitive mode and forms six hydrogen bonds with ACE. The present study demonstrates that the hypotensive effects produced by the cutlery are attributed to these peptides. 377 Identification of novel ACE inhibitory peptides from Pacific saury: In vivo antihypertensive effect and transport route. Dual inhibitory properties of mechanically boneless chicken residue (MDCR) hydrolysate on angiotensin-I converting enzyme (ACE-1) and dipeptidyl peptidase 4 (DPP4). Using food-grade protease to hydrolyzate MDCR, a potent peptide with dual inhibitory effects on ACE-1 and DPP4 was identified and then isolated to obtain IY (ACE-1-inhibitor) and VL (DPP4-inhibitor) peptides with dual effects on blood pressure and blood glucose regulation. Low Molecular Weight Peptide Fraction from Poultry Byproduct Hydrolysate Features Dual ACE-1 and DPP4 Inhibition. 378

Peptide drugs acting on GPIIb /IIIa receptors

Eptifibatide, a ring heptapeptide derived from a protein in the venom of crotchtails, can be specifically recognized by GPIIb /IIIa receptors on the surface of platelets, blocking the binding of fibrinogen to GPIIb /IIIa receptors and inhibiting the final pathway of platelet aggregation. Its ring structure increases the bioavailability of the drug and its resistance to plasma proteases. 379 , 380 It has been approved by the FDA for clinical use in Acute Coronary syndrome (ACS), including heart attacks and other emergencies such as sudden cessation of blood supply to the heart. 381 , 382

Acute coronary syndromes are recognized by damage to the walls of the coronary arteries, resulting in the formation of intraluminal thrombi that block one or more coronary arteries, leading to unstable angina, non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction. 9 Antiplatelet therapy may be a therapeutic basis for the prevention and treatment of recurrent cardiovascular events in patients with acute coronary syndrome and undergoing percutaneous coronary intervention (PCI). In addition, it has been shown that intracoronary eptifibatide combined with PCI in the treatment of non-ST-segment elevation-acute coronary syndrome (NSTE-ACS) can effectively improve blood flow, increase myocardial perfusion to a certain extent, reduce perioperative platelet aggregation, which can improve cardiac function, with better results than PCI alone, besides, it has a better safety profile than that of abciximab. 383 , 384 Furthermore, compared with the non-peptide small molecule GPIIb /IIIa receptor antagonists orbofiban, xemilofiban, sibrafiban and roxifiban (high side effects, such as thrombogenicity and high mortality), 385 eptifibatide has little antigenicity. 386 Eptifibatide has stronger binding ability to GPIIb /IIIa receptors, better safety, and faster action. The results of comparative experiments showed that intravenous administration of eptifibatide avoided the pre-systemic metabolism of liver and gastrointestinal enzymes, resulting in complete systemic availability. At a given dose, the pharmacokinetics of eptifibatide is linearly dose-dependent, and the antiplatelet activity of regular doses of eptifibatide is superior to that of tirofiban (GPIIb/IIIa inhibitor). 379

Peptide drugs acting on tyrosine kinase receptors

Neuroglial protein (NRG)-1, also known as neural differentiation factor (NDF) or glial growth factor (GGF), is expressed in the cardiovascular system, nervous system, gut, kidney, and mammary gland. 387 , 388 It is a ligand for tyrosine kinase receptors of ErbB3 and ErbB4 and structurally belongs to the epidermal growth factor (EGF) family. It directly binds to the ErbB4 receptor on cardiomyocytes, which activates the receptor and produces the corresponding bioactivities. The NRG-1/Erb B signaling system is not only involved in the regulation of cardiac embryonic development, but also closely related to the formation of cardiac structure, the maintenance of cardiac function, and the development of heart failure. Recombinant human neuromodulin (rhNRG)-1 peptide can attenuate myocardial injury in various animal models of cardiomyopathy. Additionally, it has therapeutic effects on heart failure. Phase II (CTR20192276) and phase III ( NCT05949801 ) clinical trials of rhNRG-1 in heart failure are in progress.

Advance of peptide-based therapeutics in infection

Anti-infection is an important area of therapeutic peptides. The infection is caused by pathogens such as bacteria, viruses, fungi, parasites, etc. Infectious diseases are one of the major challenges in current clinical medicine. Penicillin is the first anti-infective drug applied in the clinic in the world. After years of development, more and more antibiotics have sprung up and made significant contributions to the cause of resisting bacterial infections for all mankind, but the problem of drug resistance caused by the misuse of antibiotics has also gradually come to the fore. In 2019, it is estimated that nearly 5 million deaths were related to antimicrobial resistance, of which 1.27 million were directly caused by antimicrobial resistance. At the same time, “superbugs” are constantly expanding outwardly. As a result of drug resistance, antibiotics and other antimicrobial medicines become ineffective and infections become increasingly difficult or impossible to treat. 389 , 390 The development of new antibiotics is insufficiently motivated globally, and there is an urgent need for new anti-infective drugs, which makes the research on antimicrobial peptides one of the current hotspots. More than 3000 antimicrobial peptides (AMPs) have been identified to date. Among them, gramicidin, daptomycin, colistin, vancomycin, oritavancin, dalbavancin and telavancin has been approved by the FDA for the treatment of bacterial infections. 391

Antimicrobial peptides (AMPs), as a class of possible alternatives to antibiotics, are good candidates for overcoming antibiotic resistance due to their high antimicrobial activity, broad antimicrobial spectrum, variety, specificity, and the fact that the target strains are not prone to resistant mutations. 392 It is a small molecule peptide that plays an important role in the host innate immunity. Most AMPs are short (10-50 amino acids), possess a positive charge (ranging from 2 to 11), and contain a large percentage of hydrophobic residues (usually 50%). 391 , 393 , 394 Structurally, AMPs have α-helical, β-sheet, or extended/random-coil structures. 395 – 397 Traditional antibiotics target an enzyme or a protein along a metabolic pathway, however, bacteria can produce new proteins through genetic mutations and thus become resistant to the drug, most antimicrobial peptides act by disrupting the membrane integrity of the target organisms and/or by transmigrating across microbial membranes to reach intracellular targets. 398 Most antimicrobial peptides can kill microbial pathogens directly and the antimicrobial action of antimicrobial peptides tends to be very rapid, e.g., tick-defensin-derived Os(3-12)NH2 and computer-designed PaDBS1R1 peptides both kill microorganisms within 5-10 minutes of the exposure. 399 , 400 Moreover, many of these antimicrobial peptides have a wide spectrum of antimicrobial effects, including activity against gram-positive and gram-negative microorganisms, fungi, unicellular protozoa and viruses. Also, some AMPs exhibit immunomodulatory activity, resulting in the indirect facilitation of pathogen clearance from the host. 400 – 403

In terms of AMPs structure, the net positive charge of AMPs is capable of electrostatic interaction with negatively charged microbial membranes, and it has low selectivity to neutrally charged mammalian cell membranes. The hydrophobic residues enable them to penetrate cells and induce membrane cleavage. Meanwhile, the increased hydrophobicity of amino acid sequences can also reduce the selectivity and toxicity to mammalian cells. 404 In fact, AMPs still contain some anions. However, its mechanism of action is difficult to determine, and it still has a significant role in anti-infection. In addition to their antimicrobial properties, AMPs play a pivotal role in intracellular processes such as angiogenesis, arteriogenesis, inflammatory responses, cell signaling, and wound healing, which makes them interesting candidates for research and development of the innovative drug. 405 – 407

Antibacterial mechanisms

As mentioned above, most AMPs contain a net positive charge, a considerable proportion of amino acid hydrophobic residues, and contain α-helix, β-sheet and other secondary structures, which play an important role in antibacterial and anti-infection. 404 It has great prospects in the field of anti-infection. At present, the mechanism of action of AMPs mainly includes two modes of action: Membrane action model and non-membrane action model. 408 , 409 In membrane interaction models, disruption of microbial membranes by AMPs can occur through different mechanisms, including disruption of the lipid bilayer (barrel-stave model and toroidal-pore model), thinning of the membrane lipid bilayer, and subsequent membrane solubilization (carpet model, and aggregate model). 410 On the other hand, some AMPs do not rely on a direct membrane breakdown mechanism but pass through the bacterial cytoplasmic membrane without necessarily disrupting it, then it interferes with fundamental processes such as DNA and protein synthesis, or inhibit other intracellular targets. 411 , 412 Of these, binding of AMPs to bacterial cell membranes occurs through electrostatic interactions between cationic AMPs and anionic lipopolysaccharides (lipopolysaccharides from gram-negative bacteria) or (lipoblasts and peptidoglycans from gram-positive bacteria), and the subsequent invasion of AMPs into the cell exerts their respective interactions to achieve anti-infective properties. 413 Nowadays, a variety of peptide antibiotics and non-antibiotic anti-infective drugs are under pre-clinical feasibility study or marketed for the treatment of infectious diseases.

Classical AMPs

Daptomycin, a cyclic lipopeptide antibiotic developed and marketed by Cubist Pharmaceutical Company in 1987, is a classic antimicrobial peptide drug. It has become the world’s first cyclic lipopeptide antibiotic and it is the first-line drug for the treatment of infections caused by drug-resistant Gram-positive bacteria. In 2003, daptomycin was approved for use in the United States for the treatment of complex and structural skin infections caused by gram-positive bacteria, as well as bacteremia and right-sided endocarditis caused by Staphylococcus aureus. 414 Daptomycin mainly acts on the cell membrane of gram-positive bacteria. Within neutral pH, daptomycin has a negative charge and its antibacterial activity is dependent on calcium ions. When daptomycin is close to the bacterial cell membrane, it oligomerizes under the action of calcium ions and forms an “ion channel” like structure on the cell membrane, which causes intracellular ions to flow out, rapidly depolarizes the cell membrane, and blocks the synthesis of RNA, DNA and macromolecular proteins, and finally, bacterial death due to these factors. 415 – 417 In addition, surotomycin, optimized by the fatty acid side chain of daptomycin, has been shown to have a rapid bactericidal effect on Clostridium difficile infection (CDI). It is currently in phase III clinical trials for the treatment of CDI. 418 – 420

Dalbavancin (Xydalba ® ), a second-generation, semi-synthetic lipoglycopeptide antibiotic, has strong antibacterial activity against a variety of gram-positive bacteria (including methicillin-resistant Staphylococcus aureus MRSA and Streptococcus pyogenes) and some streptococci, with a long half-life and good tolerance. 421 , 422 Xydalba ® was approved by the EMA in 2015 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Interestingly, dalbavancin, one of the star drugs in the field of antibiotics, was first discovered and developed by Vicuron company in the United States, and then passed through Pfizer and Durata Company before it was approved by the FDA in May 2014. Based on the positive results of two randomized, double-blind and multi-center clinical trials (SOLO I and SOLO II trials), FDA approved a new antibiotic, which is named Oritavancin in the same year. 423 – 425 Oritavancin injection for the treatment of ABSSSIs caused by gram-positive bacteria (including methicillin-resistant Staphylococcus aureus, MRSA) in adult patients. Oritavancin and dalbavancin (approved by the FDA in 2014), as well as the vancomycin (approved by the FDA in 1954), are belong to the new second-generation, semi-synthetic glycopeptide antibiotics. Notably, it is the first and only antibiotic for the treatment of ABSSSIs with a single-dose regimen. 423

Rezafungin (Rezzayo ® ) was approved by the FDA in March 2023 for the treatment of candidemia and invasive candidiasis in adults, the first therapeutic treatment approved for invasive candida infections in nearly a decade. 426 Rezafungin is a novel echinocandin that acts by inhibiting β-1,3-glucose synthetase thereby disrupting the integrity of fungal cell wall. 427 , 428 The approval of this drug further expands the application of AMPs in the field of anti-infectives. Besides, there are some promising AMPs under study.

The antimicrobial peptide peceleganan (PL-5) spray is a non-antibiotic anti-infective drug. As a new type of peptide broad-spectrum anti-infective drug, it has a unique bactericidal mechanism. 429 It acts as a bacterial penicillin binding proteins family inhibitor (PBPs inhibitor), showing strong bactericidal advantages against gram-positive, Gram-negative and various antibiotic-resistant bacteria. It can be used for various wound infections such as burns, traumatic ulcers, venous ulcer infections and Wagner class II diabetic foot ulcers, etc. Currently, antimicrobial peptide PL-5 spray is in the U.S. Phase II clinical study ( NCT06189638 ), which is expected to achieve better results.

Teixobactin, a novel peptide antibiotic obtained by screening bacteria from soil samples has a wide range of activity against multi-drug resistant gram-positive pathogens such as methicillin-resistant staphylococcus aureus, streptococcus pneumoniae, and vancomycin-resistant enterococci. 430 Teixobactin targets the peptidoglycan precursor lipid II, which has the dual effect of inhibiting peptidoglycan synthesis and disrupting cell membranes, enabling an effective attack on bacterial cell membranes. 431 – 433 Antimicrobial experimental studies in vitro have shown that teixobactin has a good inhibitory effect on gram-positive bacteria and is non-toxic to mammalian cells, as well as non-hemolytic and non-genotoxic, which make it a promising drug lead-compound. 434

Recently, Li et al. reported that CT-K3K7, a scorpion antimicrobial peptide derivative, was able to inhibit the growth of Candida both in vitro and in vivo. CT-K3K7 can kill Candida by destroying cell membrane or nucleus and interacting with nucleic acid. It can also induce candida cell necrosis and inhibit its mycelium and biofilm formation through reactive oxygen species (ROS)-related pathways. In the mouse model of subcutaneous infection, CT-K3K7 significantly prevented skin abscess formation and reduced the number of recovered Candida cells in the infected area. Therefore, CT-K3K7 is expected to be a promising drug for the treatment of Candida skin infections. In addition, there are a number of AMPs derived from natural sources, as well as AMPs from engineered sources, that play an important role in the field of anti-infection. Such as the rhesus theta-defensin-1 (RTD-1), 435 , 436 a natural macrocyclic AMP expressed in primate leukocytes. Its macrocyclic structure confers drug stability and resistance to cleavage by the large number of proteases found in the saliva of cystic fibrosis (CF) patients, furthermore, it is more effective than the usual natural AMPs. In addition, RTD-1 showed rapid in vitro bactericidal activity against mucoid, non-mucoid and multi-drug resistant clinical isolates of Pseudomonas aeruginosa, without cross-resistance to colistin. Nowadays, it is considered as a potential therapeutic agent for CF airway infections. WLBU2 is a cationic amphipathic peptide with membranolytic activity composed of Arginine, Valine and Tryptophan in different arrangements. 437 Due to its broad-spectrum antimicrobial activity against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) pathogens. 438 – 440 the molecule is currently in Phase I clinical trials ( NCT05137314 ) for the treatment of periprosthetic joint infections.

Overall, AMPs have been initially used in the field of biomedicine research with their unique advantages. AMPs not only have certain inhibitory effects on bacteria, fungi and anti-parasites, but also a certain inhibitory and killing effects on enveloped viruses and tumor cells. The broad-spectrum antibacterial activity of AMPs has been studied as an alternative to antibiotics. It is believed that AMPs will be more rapidly developed in the field of biomedicine in the near future.

Advance of peptide-based therapeutics in anti-coronavirus

Currently, the coronaviruses(COVs) that infect humans (HCoVs) contain seven COVs. 441 Within these, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and SARS Coronavirus (SARS-CoV) are highly pathogenic COVs that can cause serious illness and even death. In contrast, HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 are considered low pathogenic HCoVs as they usually cause mild disease in humans. 442 Novel Coronavirus 2019 (COVID-19), which is caused by SARS-CoV-2 infection, has led to about 770 million diagnosed cases and more than 7 million deaths worldwide as of January 24, 2024 (From https:// covid19.who.int). For the prevention and treatment of COVID-19, there are three dominant antiviral options: vaccines, neutralizing antibodies, and small molecule drugs. 443 Among them, vaccines can realize early prevention to a certain extent, neutralizing antibodies are expected to be able to directly block the invasion of the virus into the host cell, while small molecule drugs can block the replication of the virus in the host cell by targeting the core shared proteins, which play a therapeutic role in post-infection treatment and disease control. 444 It is hoped that long-term effective and broad-spectrum small molecule drugs can be developed. With regard to vaccines and neutralizing antibodies, SARS-CoV-2 continues to spread globally with the mutation of the new COVs, and new variants are still emerging rapidly, posing a major challenge to current vaccine and therapeutic approaches. Thus, this calls for a sustained supply of highly effective, low-toxicity antiviral drugs to combat SARS-CoV-2 and its variants. Peptide drugs are gaining attention in the development of anti-SARS drugs due to its low immunogenicity, low cost, specificity and modularity enabling it to be tailored to the virus.

Development of anti- COVs candidate targets

In the process of viral invasion, viruses need to enter the target cells through the steps of receptor recognition and membrane fusion or endocytosis, in which the receptor-binding subunit of the viral surface protein (SP) plays a role in mediating the recognition between the virus and the cell receptor, and the transmembrane subunit of the viral SP plays a role in mediating the fusion of the membrane, which are the common antiviral targets in this process. In addition, there are receptors on the cell, host cell proteases needed to cleave the SP, and so on. After the virus enters the target cell, it releases its own DNA/RNA into the cell, which serves as a template to direct the synthesis of viral proteins. At the same time the viral genome undergoes simultaneous self-replication. During this process, certain viral proteases act to cleave viral precursor proteins, while RNA viruses require RNA-dependent RNA or DNA polymerases (RdRp and RdDp) for replication. The RdRp and RdDp are not present in the human body, so viral proteases as well as RdRp and RdDp are also important antiviral targets. Then, the newly synthesized viral genome and viral proteins assemble into new viral particles, which are released to the outside of the cell for dissemination through budding or cell trafficking pathways. Within the same viral genus, the sequences and structures of proteins that perform the same function are often highly similar, such as the spike (S) protein structures of SARS-CoV and SARS-CoV-2. These proteins often serve as common targets for the development of antiviral drugs. 445

The protein structure of COVs includes structural proteins and Non-structural proteins (NSPs). The structural proteins are composed of the spike (S) protein, envelope (E) protein, membrane (M) protein and nucleocapsid (N) protein. 446 Theoretically, all the COVs enzymes and proteins involved in viral replication and control of the host cell machinery are potential drug targets, including S protein, papain-like protease (PL Pro ) and master protease (M pro /3 CL pro ), and viral RNA-dependent RNA polymerase (RdRP). This chapter focuses on the use of peptides in COVID-19, with a brief overview of hot peptide targets in COVID-19.

A) The S protein, a key protein in COVs, and its role

The coronavirus spike S protein plays an important role in the invasion of COVs. Similar to other COVs, SARS-CoV-2 infection requires the fusion of the viral envelope and cell membrane, which is mediated by the viral spike (S) glycoprotein. 447 It regulates viral entry into host cells and is also the major antigenic determinant, often the target of the host antibody response. The COVID-19 is caused by severe acute respiratory SARS-CoV-2 infection. S protein is an important protein that mediates virus entry into cells. The receptor binding domain (RBD) on the S1 subunit is responsible for the binding of the virus to the cell surface receptor. 448 – 451 Many neutralizing antibodies target this region to inhibit RBD binding to the viral receptor, thereby blocking COVs infection. However, this region is not conserved and there is great variability among COVs, which makes most of the neutralizing antibodies targeting this region lack broad-spectrum and can only inhibit one or a few COVs. 446 The heptad repeat 1/2 (HR1/HR2) region of the S2 subunit can interact with each other to form a six-helix structure, which mediates the fusion of the virus with cells and the entry into cells for replication. The formation of the homologous hexahelix can be blocked by the addition of exogenous peptides that can interact with the HR1 or HR2 region of the S2 subunit, thereby inhibiting the invasion of the virus into cells. In addition, the mechanism of membrane fusion between virus and target cells is very conserved in different COVs, and the six-helix bundle formation between the HR1 and HR2 domains plays a key role in driving membrane fusion, which also makes this region an important target for the development of broad-spectrum viral fusion/invasion inhibitors.

In addition, researchers found that the affinity of the S protein of SARS-CoV-2 to the human Angiotensin-converting enzyme 2 (ACE2) receptor was much higher than that of SARS. 448 Based on the researchers’ elucidation of the electron microscopic structures of the full-length proteins of the ACE2-B0AT1 complex and the ACE2-RBD complex, which revealed how the S protein of 2019-nCoV interacts with the receptor ACE2 at the atomic level, the structural basis and functional characterization of the entry of SARS-CoV-2 into the target cells were further clarified. The above results show that 2019-nCoV enters human cells by targeting the receptor domain (RBD) of the viral transmembrane S protein to the receptor protein, ACE2. In other words, the interaction between S protein and ACE2 is the key way for the virus to enter cells. ACE2 is like the “door handle”, and SARS-CoV-2 opens the door to enter human cells by grasping the “door handle”. Therefore, blocking the interaction between ACE2 and 2019-nCoV S protein can be used as one of the potential effective ways to prevent and control COVID-19.

B) 3CL protease (3C-like protease, 3CL PRO , or M pro )-a key enzyme in COVs replication

COVs are enveloped viruses with a positive-stranded, single-stranded RNA genome of 26 to 32 kb in length. During SARS-CoV-2 infection of the host, the S protein on the outer surface of the viral particles is responsible for binding to the host receptor for attachment to the cell membrane, followed by fusion of the viral and host cell membranes and release of the viral genomic RNA into the cell. Next, there is fusion of the virus and host cell membranes and release of viral genomic RNA into the cell. Subsequently, two viral replicase polyproteins are translated into two polyproteins, pp1a and pp1ab, by controlling the production of two viral replicase polyproteins by host ribosomes. 452 These can be further processed by viral-encoded proteases in 16 mature nonstructural proteins (NSPs). The main protease (M pro ), or 3C-like protease (3CL pro ), is an extremely important protease in the propagation of other coronaviruses, such as Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which is responsible for the cleavage of protein precursors of the translated viral genome, resulting in a number of nonstructural proteins (NSPs), that assemble to form the viral replication-transcription enzyme complex NSPs. Finally, these non-structural proteins are assembled to form the viral replicase-transcriptase complex (RTC). 453 Therefore, 3CL pro inhibitors can be developed to inhibit the activity of 3CL pro and interfere with the viral replication process. Moreover, since of 3CL pro is highly conserved among different genera of COVs and has no homologous proteins in the human body, it implies that the design of inhibitors by using it as a drug target can achieve a better expectation of selectivity and safety, and it has a great potential to be explored, which has become the direction of research in the field of human in the anti-coronaviral field.

Peptides for coronaviruses (COVID-19 as an example)

Paxlovid ® is currently the only peptidomimetic drug approved by the FDA for severe symptoms caused by COVID-19. In December 2021, Emergency Use Authorization (EUA) of Paxlovid by the FDA for the treatment of SARS-CoV-2 in mild-to-moderate adults and pediatric and adult patients ≥12 years of age with a body mass of ≥40 kg, and in patient populations at higher risk of severe disease. 454 , 455 Preliminary results of a phase III clinical trial showed that patients who were treated within 3 days of symptom onset had an 89% lower risk of hospitalization and death from any cause than those who received placebo. 456 Until May 2023, the drug was formally approved by the FDA from Emergency Use Authorization (EUA).

In fact, Paxlovid ® is a COVID-19 combination product, a combination of the 3CL protease inhibitor PF-07321332 (also known as Nirmatrelvir) and low-dose Ritonavir, both peptide analogues. 455 , 457 Development of PF-07321332 began with the SARS-CoV outbreak in 2002. During the SARS-CoV epidemic period, Pfizer’s researchers tried to design SARS-CoV 3CL protease inhibitors based on Rupintrivir (an irreversible inhibitor of human rhinovirus 3CL protease) as the starting point. After a series of optimization, PF-00835231 was obtained. However, the inhibitor has not yet been tested in animals, and it has been shelved due to the demise of the SARS-CoV epidemic. It was restarted in 2020 due to the outbreak of COVID-19. Ritonavir was developed to solve the problem that multiple sites of PF-07321332 are oxidized and metabolized by CYP3A4 (cytochrome P450 3A4 enzyme) in liver microsomes. 457 , 458 Ritonavir, as a pharmacokinetic enhancer of Nirmatrelvir, slows down its breakdown in vivo and enhances its half-life and bioavailability by inhibiting the degradation of Nirmatrelvir by CYP3A4. so that it remains active in the body for a longer period of time and at higher concentrations to help fight the virus. 455 , 459 This strategy is also borrowed from previous antiviral drug delivery strategies. Efficacy data from the phase II/III study of Paxlovid showed an 86% reduction in the risk of COVID-19-related hospitalization or death from any cause among patients who received Paxlovid ® within five days of symptom onset. Oral Paxlovid is superior to intravenous treatments such as Remdesivir (approved by the FDA in October 2022), 460 as well as lower hospitalization and mortality rates than Molnupiravir (approved by the FDA in 2022), since then, Paxlovid ® (PF-07321332 and Ritonavir) was born and remains relevant for the treatment of COVID-19 and some of its variants. This antiviral therapy has also been derived from the oral anti-COVID-19 innovative drug Simnotrelvir/Ritonavir, which is safe and effective, and has shown remarkable efficacy and safety in clinical II/III trials.

EK1 polypeptide, a peptide inhibitor developed by Jiang et al., broadly inhibits multiple human COVs capable of infecting humans, which binds to the HR1 region of a variety of coronaviruses to form a hetero-hexamer. Thus, it competitively inhibits the formation of hexamers from the HR1/HR2 interaction of the virus itself, thereby inhibiting the fusion of the virus with the host cell and preventing the entry of the virus’ genes into the cell for replication. After the outbreak of COVID-19, they demonstrated that EK1 peptide can also bind to the HR1 of SARS-CoV-2 and efficiently inhibit the invasion and infection of SARS-CoV-2 into host cells. 461 Currently, the EK1 nebulizer is about to enter a Phase IIa clinical trial. Besides, by modifying with palmitic acid or cholesterol, Jiang/Lu et al. have further developed a series of more efficient and broad-spectrum lipopeptide fusion/invasion inhibitors, such as EK1C4, EKL1C, and EK1-C16, which are equally effective in inhibiting the infection of various SARS-CoV-2 variants without being affected by variants. 462 , 463

In addition to the HR1 region, the HR2 region is also an important target for the development of viral fusion/invasion inhibitors. However, the HR1-derived peptides contain too many hydrophobic amino acids to maintain a stable α-helix structure in aqueous solution. Therefore, they designed a protein inhibitor targeting the HR2 region of SARS-CoV-2, 5-helix (composed of two HR2 and three HR1-derived protein fragments), which can bind to the HR2 region of SARS-CoV-2 to form a heterologous six-helix bundle and inhibit the invasion of the virus into host cells. Like the EK1 peptide, nCoV-5-helix can also effectively inhibit the infection of various SARS-CoV-2 variants, including Omicron and Delta. 464 Compared with common neutralizing antibody drugs, peptide-based inhibitors have the following obvious advantages: (1) Peptide-based inhibitors act on the conserved HR1/HR2 locus, which allows peptide-based inhibitors to demonstrate broader-spectrum COVs inhibitory activity than targeting RBD/NTD-neutralizing antibodies; (2) Peptide-based inhibitors have shorter amino acid sequences and smaller molecular weights, which can be directly synthesized by chemical synthesis, greatly reducing the time and production cost; Moreover, it can directly inhibit the replication of COVs in the patient’s lung by intranasal administration. (3) high safety and efficacy, basically equal to antibody drugs. The only drawback is that the half-life of peptide drugs is shorter than that of antibody drugs. (4) Peptide-based inhibitors are more stable and can be stored for a long time at room temperature, with lower storage and transportation costs. Therefore, the development of Pan-CoV fusion/invasion inhibitors can effectively prevent and treat SARS-CoV and its variants, SARS-CoV and MERS-CoV infections.

HY3000 was developed in the early stage of the COVID-19 outbreak. Based on the analysis of the membrane fusion mechanism of SARS-CoV-2, SARS-CoV,MERS-CoV. 465 – 467 Gao et al. designed a polypeptide inhibitor P3 targeting SARS-CoV-2 HR1, which can inhibit theinfection of SARS-CoV-2, 467 but peptide P3 has insufficient activity. In order to further improve the activity of P3 peptides and develop anti-SARS-CoV-2 polypeptide membrane fusion inhibitors, researchers designed many P3 derivatives based on their structure, finally, they found that the antiviral activity of P315 peptide was the best, which was about 8-fold higher than that of P3. Furthermore, through PEG and cholesterol modification, the P315V3 lipopeptide with about 1000-fold higher activity was obtained (HY3000). 468 It can bind to the HR1 region of the S protein of SARS-CoV-2 and inhibit membrane fusion to prevent the virus from entering the cell interior. At the same time, the hydrophobic tail of HY3000 can be fixed to the surface of the cell membrane, forming a protective barrier at the cell surface. Besides, it can effectively inhibit novel COVs variants, including XBB.1.5. In addition, it can inhibit SARS-CoV, MERS-CoV and seasonal COVs HCoV-NL63, HCoV-229E and HCoV-OC43, HY3100 shows a broad spectrum of COVs. Based on the effective antiviral effect, HY3000 nasal spray was approved by NMPA for phase I clinical trial in August 2022. Now, the phase I clinical trial has been completed and the drug shows enough safety. Based on it, it is currently under clinical phase II trial in China. Furthermore, HY3000 was accepted by the US FDA clinical trial in January 2023.

As mentioned above, targeting the most conserved HR1 region of SARS-CoV-2 can be an important target for the development of broad-spectrum viral fusion/invasion inhibitors. By using the membrane fusion mechanism, researchers developed a peptide YKYY017 (from SARSCoV-2 HR2-deriving lipopeptides, IPB20) 468 , 469 that targeted the conserved HR1 region and competitively bound to the viral HR1 region, then YKYY017 prevents the formation of the viral homologous six-helix bundle (6-HB) structure, and blocks the fusion process between the virus and host cells. It can inhibit two membrane fusion pathways, cell surface and endosomes, to exert antiviral effects. In vitro pharmacodynamic studies showed that YKYY017 had significant and broad-spectrum inhibitory effects on the original SARS-CoV-2 strain and its epidemic variants (Delta, Omicron BA.1, BA.2, BA.4 and BF.7). YKYY017 has a broad spectrum against cold-causing coronaviruses (HCoV-NL63, HCoV-229E, etc.), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and bat-derived coronavirus RaTG13), pangolin-derived coronaviruses (PCoV-GD, PCoV-Gx), it has also shown significant inhibitory effects, reflecting the broad-spectrum anti-coronavirus activity. Toxicological studies showed that YKYY017 had no obvious toxicity and related adverse reactions, as well as a good therapeutic and preventive effects. It is currently in Phase II/III clinical trial in China (ChiCTR2300075467) and was approved for clinical investigation on May 12th, 2023. As a new generation of COVs membrane fusion inhibitor with broad spectrum, YKYY017 aerosol inhalation is expected to be well used in the fight against SARS-CoV-2 and its variants.

Recently, Dang et al. developed a new broad-spectrum SARS-CoV-2 fusion inhibitor, A1L35HR2m-Chol, which can effectively inhibit different SARS-CoV-2 mutant strains, as well as SARS-CoV and MERS-CoV. 470 The researchers interconnected the ACE2-derived peptide A1 with the N-terminus of the HR2m peptide via a flexible junction (GGGGS)7 of the appropriate length to generate A1-(GGGGS)7-HR2m (A1L35HR2m), (HR2mL35A1) was then obtained by exchanging the positions of the A1 peptide and the HR2m peptide. In addition, two other fusion peptides were constructed by shortening the length of the junction to derive A1L5HR2m and A1HR2m. The researchers then evaluated the ability of A1L35HR2m, HR2mL35A1, A1L5HR2m, and A1LHR2m to inhibit SARS-CoV-2 by the SARS-CoV-2 pseudotyped virus infection assay. It was found that the addition of ACE2-derived peptide A1 to the N-terminus of HR2m peptide with a long flexible junction significantly increased the anti-SARS-CoV-2 activity.

This research revealed that the antiviral mechanism of A1L35HR2m may be similar to that of HR2-derived peptides, which can enhance the competitive interaction with the affinity of HR1 structural domains to block the fusion of viruses with target cell membranes. Meanwhile, adopting the S protein-mediated cell-cell fusion assay, it was found that A1L35HR2m-Chol effectively inhibited SARS-CoV-2 D614G S protein-mediated cell fusion between 293 T/EGFP/S and Caco-2 cells, which contributes to the enhancement of the viral activity; moreover, the researchers also performed site-specific modification of the C-terminus of A1L35HR2m to generate A1L35HR2m, which is an anti-viral peptide that can be used to prevent the virus from fusing with the target cell membrane. The results showed that A1L35HR2m-Chol exhibited broad and effective inhibitory activity against different SARS-CoV-2 VOC, SARS-CoV and MERS-CoV, and did not show in vitro or in vivo toxicity.As well, the level of A1L35HR2m-Chol dose had no effect on the hepatic and renal functions of the mice.

In general, peptides against acute respiratory distress syndrome (ARDS) caused by coronaviruses and related respiratory problems caused by SARS-COV-2 infection, most of them are target-based synthetic peptides. Researchers have been working on the development of peptide therapeutics for a variety of diseases, including Covid-19, due to their ease of synthesis, high target specificity, selectivity, and low toxicity, etc. In addition, a peptide-based Covid-19 vaccine is in clinical trials. Finally, a number of novel peptide drug delivery systems with high potential for other disease development. Peptide drugs are expected to be further developed in the future.

Advance of peptide-based therapeutics in digestive diseases

The use of peptide drugs in gastrointestinal diseases is mainly focused on the control of acute upper gastrointestinal bleeding (such as somatostatin analogues and vasopressin analogues) and other intestinal diseases (Linzess ® , Trulance ® ).Vapreotide (Sanvar ® ), a synthetic somatostatin analogue, was approved in Mexico in 2004. 471 , 472 In addition, a phase III clinical trial found that the combination of Vapreotide and endoscopic therapy was more effective than endoscopic therapy alone in controlling acute bleeding in patients with cirrhosis and variceal bleeding. 473 Terlipressin (Terlivaz ® ) is a synthetic vasopressin analogue developed by Ferring Pharmaceuticals, which can be used to treat gastrointestinal variceal bleeding. In terms of anti-gastrointestinal bleeding, the main focus is on bleeding caused by cirrhosis. 474 It was approved by the FDA in 2022 to improve the rapid decline in renal function in adult patients with hepatorenal syndrome (HRS). 475

In addition, peptides have been shown to be effective in irritable bowel syndrome (IBS). Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disease characterized by smooth muscle dysfunction, which is prone to relapse and has a high incidence worldwide. “IBS is characterized by persistent or intermittent episodes of abdominal pain, bloating, and abnormalities in bowel habits and stool form, without morphological or biochemical abnormalities.” Linaclotide (Linzess ® ) is a guanylate cyclase-C (GC-C) agonist, which is a 14-amino acid polypeptide. 476 , 477 Linzess ® was approved by the FDA in December 2012 for the treatment of adult patients with constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). It is also the first new prescription drug approved for the treatment of adult patients with moderate to severe IBS-C in Europe. Linzess ® and its active metabolites have been shown to bind to guanylate cyclase-C (GC-C) receptors on the luminal surface of the small intestinal epithelium, leading to the activation of GC-C and the increase of intracellular and extracellular concentrations of cyclic guanosine monophosphide (cGMP). Intracellular cGMP increases the secretion of chloride and bicarbonate in the small intestine by activating the cystic fibrosis transmembrane conductance regulator (CFTR), which eventually leads to increased secretion of intestinal fluid and accelerated intestinal transport. Through GC-C activation, linaclotide reduced intestinal pain and increased gastrointestinal transit speed in animal models. Extracellular cGMP can reduce the activity of painful nerve fibers and alleviate visceral pain in animal models. 478 , 479

In January 2017, the FDA approved Trulanc ® (plecanatide), a GC-C (guanylate cyclase-C) agonist with linaclotide, for CIC (Chronic Idiopathic Constipation). 479 , 480 Plecanatide is as effective as linaclotide in the treatment of CIC but not as effective as linaclotide in the treatment of IBS-C. 481 In terms of structure, Plecanatide and Linaclotide are both small molecule monopeptide, but with one less disulfide bond, which is easier to synthesize. However, Plecanatide has a higher dosage than linaclotide in the indication of IBS, which is expected to be further optimized in future studies.

Elsiglutide is an orally active and selective GLP-2 receptor agonist, which is an analogue of GLP-2. It can increase cell proliferation, reduce intestinal cell apoptosis, and regulate intestinal balance. 482 , 483 In a rat model, Elsiglutide ameliorated Lapatinib (HY-50898) -induced diarrhea in rats. In addition, clinical phase II studies testing elsiglutide in colorectal cancer (CRC) patients receiving chemotherapy (CT) induced diarrhea with 5-fluorouracil (5-FU) have not yet yielded results. 484 Therefore, peptide drugs also occupy a certain proportion in the field of digestive tract diseases.

Advance of peptide-based therapeutics in Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease with insidious onset, clinically characterized by memory impairment, aphasia, loss of recognition, visuospatial skills impairment, behavioral changes and other comprehensive dementia manifestations and more serious neurological impairments, which seriously affects the patient’s quality of life, and in severe cases even death. 485 It is estimated that by 2050, this number will reach 130 million. This will create a huge social burden. 486 Worse still, the main challenge in the treatment of Alzheimer’s disease is that its pathogenesis has not been fully clarified, and the more recognized hypotheses of the pathogenesis include deposition of β-amyloid (Aβ) 487 and intracellular Tau protein aggregates, 488 neuroinflammation 489 and lack of acetylcholine (Ach), oxidative stress, 490 and bio-metal dyshomeostasis, etc. 491 The Aβ deposition hypothesis suggests that the normal mechanism of Aβ removal from the brain tissue of AD patients is disrupted, leading to the accumulation of toxic Aβ in the brain tissue to form Aβ plaques, 492 and when the accumulation reaches a certain level, it triggers a series of neurodegenerative processes, such as inflammation, oxidative stress, and the deposition of Tau proteins, 493 which ultimately leads to a series of clinical conditions of AD. The establishment of the Tau protein deposition hypothesis is inextricably related to the Aβ hypothesis, which suggests that Tau protein as an important protein involved in stabilizing neuronal structures in the brain and regulating internal neuronal transport systems. Tau protein plays an important role in normal brain cell activity. 494 However, due to the Aβ deposition mentioned in the above hypothesis, Tau protein accumulates and forms abnormal protein clumps (NFTs), which severely disrupts the normal function of neuronal activity and ultimately leads to a series of AD disorders in patients. In addition, Aβ accumulations in neurons can also activate glycogen synthase kinase 3-β (GSK-3β), which phosphorylates Tau proteins and ultimately forms NFT, 495 making the clinical symptoms of AD appear gradually. At the same time, neuroinflammation exacerbates the pathological processes of Aβ accumulation, Tau accumulation and Tau phosphorylation, 496 and the pathological processes of the three hypotheses produce a synergistic effect, which leads to a persistent vicious cycle, thus exacerbating the disease process of neuronal damage. In addition, the hypothesis of reduced acetylcholine levels is also recognized as an important cause of AD. In patients with AD, cholinergic neurons in the brain degenerate, resulting in reduced Ach levels, 497 which in turn leads to a range of clinical symptoms of AD, including reduced learning and memory abilities. Currently approved therapies include cholinesterase inhibitors (rivastigmine, donepezil, tacrine and galantamine), and NMDA receptor antagonists, but even their combination provides only temporary relief of symptoms, not a cure.

The key clinicopathologic indicators of AD are amyloid plaques formed by amyloid accumulation in extracellular regions or hyperphosphorylated Tau proteins aggregated in intracellular regions, which form neural protofibrillary tangles (NFTs) in affected neurons. Amyloid plaques mainly contain amyloid β40/42 peptides, which further accumulate leading to neuroinflammation and mishandling of Tau protein. 498 , 499 Based on this, a large number of domestic and international researchers have tried to develop drugs that can remove these two toxic proteins from the brain in the hope of treating AD or slowing down the process. 500 Among them, Aβ is produced by hydrolyzing and processing amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase, which means that inhibition of β- and γ-secretase cleavage can inhibit the production of Aβ protein. In this regard, many drugs targeting secretase have entered clinical trials, 501 including CTS-21166 (CoMentis), PF-05297909 (Pfizer), LY2886721 (Lilly), and AZD3293 (AstraZeneca). The results of the clinical phase 1 trial showed that CTS-21166 reduced plasma levels of Aβ protein 502 665, and AZD3293 was also shown in the clinical phase 2/3 trial. AZD3293 also achieved the target efficacy in clinical phase 2/3 trial. 503 However, the results of Phase II/III clinical trials for many other related new drug developments have been unsatisfactory.

Peptides can intervene in the process of Aβ aggregation in a variety of ways, and thus researchers continue to plow through the field. Driven by advances in drug design and synthesis techniques, a common strategy for peptides used in the treatment of AD is to design peptides with high affinity to bind to Aβ and prevent its aggregation. These peptides can alter the conformation of Aβ or inhibit its aggregation process by interacting with it. Phages can search for potential therapeutic peptides for various diseases based on the affinity between the produced peptide and the target molecule, so researchers have used it to search for peptides with the potential to inhibit Aβ aggregation. Kiessling et al. 504 then identified several Aβ-affinity peptide ligands by phage display. 505 Another strategy is to block amyloid or peptide production by designing peptides with the core sequence of the Aβ fibrillization to suppress protein or peptide aggregation. In 2015, Prof. Kapurniotu of the Technical University of Munich, Germany 506 designed a series of peptide-based small molecule inhibitors based on the protein sequences of islet amyloid polypeptide (IAPP), a type of small molecule inhibitor that can inhibit the root causes of amyloid proteins (amyloid- beta peptide and IAPP) aggregation, thus reducing the cytotoxicity of amyloid fibrils, and providing a new idea for the treatment of Alzheimer’s disease in the clinic. Prof. Kapurniotu further deepened his research on this basis, 507 and developed a new type of cyclic peptide-based small-molecule inhibitor based on the straight-chain peptide-based small-molecule inhibitors. The optimized cyclic peptide-based small molecule inhibitor not only has high efficiency and specificity in binding and recognizing amyloid proteins, but also shows a high degree of protein hydrolysis stability in human plasma, and can cross the human blood-brain barrier in cellular models, making it a potentially effective anti-amyloid drug for the treatment of AD. In addition, chiral biomolecules have the advantage of inherent stereoselectivity, whereby the aggregation of Aβ can be hindered by modifications of chiral amino acids or peptides. Amino acid chirality can determine the folding of the peptide backbone, hydrogen bonding interactions, and even the biological functions of proteins in vivo. 508 Xue et al. borrowed graphene to structurally modify a peptide to make it pharmaceutically active and regulate Aβ40 aggregation in vitro. 509

Intracellular neuroprogenitor fiber tangles containing phosphorylated Tau proteins are a hallmark protein of AD, and hyperphosphorylation of Tau proteins causes the deposition of this characteristic protein. Meanwhile, Tau function is regulated by a variety of post-translational modifications at more than 50 sites, and Tau in healthy neurons carries multiple phosphorylation motifs that are located predominantly in its microtubule assembly domain. It has also been shown that Aβ can initiate a deleterious cascade of responses involving Tau pathology and neurodegeneration, i.e ., Tau proteins are mediators of Aβ cytotoxicity. 510 Possible synergistic effects of Aβ and Tau proteins on microglia and astrocytes, whose interactions mediate cognitive dysfunction in AD patients. Researchers have proposed multiple mechanisms of action against Tau, including specific removal of pathological Tau species, reduction of Tau production, promotion of Tau physiological function through microtubule stabilization or inhibition of post-translational modifications. 511 However, most of the Tau protein-targeting therapies tested to date have been immunotherapies that can target Tau proteins intracellularly and/or extracellularly, but targeting extracellularly alone is unlikely to be effective, 512 and no Tau-targeting therapies have yet to show definitive clinical efficacy in preclinical or early-stage AD. From the perspective of the aberrant aggregation of toxic Tau proteins, Zheng jie et al. designed and synthesized a peptide chimera drug, DEPTAC, which can specifically reduce the phosphorylation level of Tau proteins and thus promote their degradation to avoid aggregation. 513 This drug can selectively recruit protein phosphatase 2 A (PP2A) to the periphery of Tau proteins and thus induce their dephosphorylation.

Several studies have shown that neuroinflammation plays a prominent role in the pathogenesis of Alzheimer’s disease. There is a correlation between neuroinflammation and amyloid and Tau pathology. When innate immune cells are activated, programmed cell death can be induced through a variety of pathways, and cell death usually leads to the release of pro-inflammatory cytokines that propagate the innate immune response and can eliminate beta plaques and aggregated Tau proteins. 514 However, chronic neuroinflammation caused by cell death is associated with neurodegenerative diseases and may worsen Alzheimer’s disease. The continued elucidation of cell death pathways and central innate immune sensor signaling pathways involved in regulating neuroinflammation and Aβ/Tau clearance will have a major impact on the field of AD research. Recent evidence suggests an association between AD and T2DM. 515 Numerous reports have found that GLP-1 RAs improve cognitive behaviors and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. GLP-1 RAs not only reduce Aβ deposition by inhibiting Aβ production and facilitating its clearance, but also reduces inflammatory mediator. GLP-1 RAs also exert neuroprotective effects by inhibiting oxidative stress and reducing neuronal apoptosis. 515 In addition, GLP-RAs can improve the cognitive function of AD patients by enhancing learning memory and spatial orientation. 516

Though strides have been made, peptides still face some challenges in the treatment of AD at present. First, AD is a complex disease whose pathogenesis and pathological processes have not been fully clarified, so further in-depth studies are needed to identify the best therapeutic targets for peptide drugs. Second, the stability, pharmacokinetics and bioavailability of peptide drugs also need to be addressed to ensure that the drugs can effectively exert therapeutic effects in vivo.

Looking ahead, with a deeper understanding of the pathogenesis of AD and the continuous advancement of drug development technology, peptide drugs will have a broader prospect in the treatment of AD. More peptide drugs targeting AD may enter clinical trials in the future and are expected to provide new and more effective treatment options for AD patients. Meanwhile, research on the combined application of peptide drugs with other therapeutic methods also needs to be strengthened, with a view to achieving better therapeutic effects.

Advance of peptide-based therapeutics in rare diseases

Currently, there are approximately 7000 identified rare diseases. Although it is individually rare, it generally affects a significant portion of the general population (10% of the population). However, less than 6% of all rare diseases have approved treatment options, highlighting their huge unmet need for drug development. 517 , 518 Rare diseases (RDs) were often chronic, leading to lifelong disability or early death; many RDs had pediatric onset, and about 30% of children with RDs died before age 5 years. 519 70% of rare diseases are hereditary, caused by germline and somatic gene mutations. 520 A small number of rare diseases are also caused by environmental, infectious or immunologic factors (e.g., African trypanosomiasis), 521 but these will not be discussed here.

Peptides also play an important role in the treatment of rare diseases. Due to the diversity and complexity of the etiology of rare diseases, conventional drugs have limited therapeutic effects on their treatment. However, some specific peptide drugs, such as synthetic analogs or biosynthetic peptides, may have specific therapeutic effects on certain rare diseases. For example, certain rare genetic diseases may result in abnormal hormone levels, while other peptide drugs are able to regulate these hormone levels, thereby alleviating the symptoms or slowing down the progression of the disease. Therefore, the research and application of peptide drugs in the treatment of rare diseases has also attracted much attention and is expected to provide more effective treatment options for these patients. Here we focus on more recent developments.

Rett syndrome

Rett syndrome, originally proposed by Andreas Rett in 1966, is a rare progressive neurodevelopmental disorder that results in severe intellectual disability, loss of mobility, and autism-like symptoms, other features include slowed head growth, seizures, autistic features, and respiratory abnormalities. 522 , 523 Trofinetide (Daybue ® ) is a novel synthetic analog of the amino-terminal tripeptide of insulin-like growth factor I (IGF-1) that can be administered orally and is neuroprotective at minimal doses. 524 , 525 It was approved by the FDA in March 2023 for the treatment of Rett syndrome for children 2 years of age and older, Notably, it is the first and only FDA-approved treatment for Rett syndrome. 526 Studies have shown that trofinetide not only inhibits inflammatory cytokine production and overactivation of microglia and astrocytes, but also increases the amount of available IGF-1 that can bind to the IGF-1 receptor, which is beneficial for the treatment of core symptoms of Rett syndrome. 524

Generalized myasthenia gravis (gMG)

Generalized myasthenia gravis (gMG) is a disorder of neuromuscular junction transmission caused by the destruction of the postsynaptic membrane of skeletal muscle by autoantibodies at the neuromuscular junction. 527 , 528 The clinical manifestations of generalized myasthenia gravis (GMG) are fluctuating skeletal weakness and fatigue intolerance, which aggravate after activity and alleviate after rest. Local or general weakness is the main symptom. In severe cases, it involves respiratory muscles and causes respiratory failure, which is potentially fatal. Zilbrysq ® is a novel macrocyclic peptide of a C5 complement inhibitor that can be used to treat adult patients with generalized myasthenia gravis (gMG) with positive anti-acetylcholine receptor (AChR) antibodies. 526 It is also the first gMG targeting C5 complement inhibitor that requires only a once-daily subcutaneous injection, providing a simpler dosing option for patients with generalized myasthenia gravis. Zilucoplan (Zilbrysq ® ), a cyclic peptide drug, was approved by the FDA in October 2023 for the treatment of AChR antibody-positive gMG that fails to respond to other immunosuppressive therapies. 529 , 530 As a complement C5 inhibitor, zilucoplan inhibits the complement mediated neuromuscular junction injury by targeting the mechanism of action. Different from the monoclonal antibody C5 inhibitor, zilucoplan, as a peptide, can be used with intravenous immunoglobulin and plasma exchange at the same time without supplementary administration, which is a new type of peptide drug with extremely simple administration.

Short bowel syndrome (SBS)

Short bowel syndrome (SBS) is mostly caused by large area surgical resection of the small intestine or congenital bowel diseases. In this condition, the absorption capacity of small intestine is limited, which cannot meet the needs of normal growth and development of patients, and parenteral nutrition (PN) support is required. 531 , 532 Clinically, the most common disorders leading to SBS in adults are Crohn’s disease, mesenteric ischemia, radiation enteritis, postoperative adhesions, and postoperative complications. The common causes of SBS in children include congenital diseases such as necrotizing enterocolitis, volvulus, gastroschisis and intestinal atresia. 533 Nutritional therapy is a very important treatment for SBS, and parenteral nutrition is very important for the survival of infants and children with SBS. However, the related complications caused by long-term PN may endanger the life of SBS children, and more effective drugs are urgently needed to meet the clinical needs. 534 , 535

GLP-2 is a specific growth factor with intestinal protective effect, which can enhance the transport of glucose and lipid in intestinal cells, enhance nutrient absorption and promote intestinal adaptation. 536 Teduglutide is a GLP-2 analogue that was previously approved by EMV in 2012 for the treatment of short bowel syndrome and malabsorption. In February 2024, Teduglutide received NMPA approval for the treatment of short bowel syndrome in adults and children aged 1 year and older. The substitution of alanine at position 2 by glycine makes teduglutide resistant to degradation by dipeptidyl peptidase-4 (DPP-4). Thus, tidulutide has a longer half-life than GLP-2. Tidulutide can reduce the requirement of PN in SBS children, increase the tolerance of enteral nutrition (EN), help some children achieve intestinal autonomy, and has good safety and tolerance, which provides a new treatment option for SBS children suffering from PN. 537 In addition, the duration of PN is positively correlated with the incidence of catheter-related infections. The present study proves that GLP-2 plays a role in intestinal adaptation. GLP-2 is a peptide secreted by intestinal L cells after foodintake. 538 , 539 It can prevent the apoptosis of intestinal epithelial cells, thereby promoting the growth and recovery of intestinal tissue. This process of growth and repair is essential for children with SBS to achieve intestinal autonomy, which provides a new hope for reducing the dependence on PN. 540 , 541

In addition, a number of peptide drugs have been approved for the treatment of other rare diseases. For example, Etelcalcetide (Parsabiv ® ), a calicomimetic agent, was approved by the FDA in February 2017 for the treatment of secondary hyperparathyroidism in adults with chronic kidney disease (CKD) undergoing hemodialysis. 542 Glatiramer was approved in 1996 for the treatment of multiple sclerosis (MS), an immune-mediated inflammatory demyelinating disease of the central nervous system. 543 , 544 The common clinical manifestations are recurrent vision loss, diplopia, limb sensory disturbance, limb movement disorder, ataxia, bladder or rectal dysfunction, etc.). In June 2023, glatiramer acetate (Copaxone ® ) was officially approved in China for the treatment of adult patients with relapsing multiple sclerosis (MS). In addition, glatiramer acetate (Copaxone ® ) can also be used for the treatment of Rett syndrome in a phase II clinical trial ( NCT02153723 ). 545 Other therapies include pegcetacoplan (a C3 complement inhibitor, approved by the FDA in May 2021) for paroxysmal nocturnal hemoglobinuria, and terlipressin (an AVPR1A agonist, approved by the FDA in September 2022) for hepatorenal syndrome (HRS). 546

Advance of peptide-based therapeutics in orthopedic metabolic diseases

The application of peptide drugs in orthopedics is mainly focused on the treatment of osteoporosis. Among them, osteoporotic fracture (OPF) is the most serious symptom of osteoporosis, which is difficult to heal, has a high disability rate and difficult to heal, and poses a serious threat to the health of middle-aged and elderly people. Osteoporosis can be treated in two ways. On one hand, it reduces bone loss by inhibiting bone resorption; on the other hand, it decreases bone loss by increasing the number or activity of osteoblasts. However, the use of anti-bone resorption drugs alone does not restore lost bone structure. Increasing the number or activity of osteoblasts may be a more attractive approach to enhancing bone formation and promoting bone regeneration. 547

Nowadays, there are many drugs to promote bone formation, including monoclonal antibodies to sclerostin and recombinant human parathyroid hormone drugs, parathyroid hormone-related protein (PTHrP) analogs, such as Evenity ® (romosozumab), Forteo ® (teriparatide) and Tymlos ® (abaloparatide). 548 – 551 Evenity ® has the potentialside effect of increasing the risk of heart attack, stroke or death due to cardiovascular disease. Parathyroid hormone drugs have drawbacks such as a two-year use limit and a potential risk of osteosarcoma. Therefore, new strategies and methods are urgently needed for the research and development of drugs for bone formation. YLL3 and YLL8 are “osteogenic specific” peptides discovered by Yao et al. through the OBOC (One Bead One Compound) library. YLL3 and YLL8 not only have high affinity for osteogenic progenitor cells, but also activate the phosphorylation of the pro-survival factor Akt. In vitro experiments confirmed that YLL3 and YLL8 can increase the differentiation and maturation of osteoblasts. Moreover, YLL3 and YLL8 can target endogenous osteogenic progenitor cells for bone regeneration therapy. 547

In addition, Osteogenic Growth Peptide (OGP) is also very effective in preventing osteoporosis. OGP is a peptide composed of fourteen amino acid residues which is a promoter of systemic response to bone marrow injury. Osteogenic growth peptide and its C-terminal pentapeptide OGP (10-14) can up-regulate the mRNA expression of type I collagen, bone calcium and alkaline phosphatase in osteoblast-like cells. 552 At the same time, it can significantly increase the content of collagen, osteocalcin, calcium and alkaline phosphatase activity of cells, promote bone formation and inhibit bone resorption, increase the number of osteoblasts, and reduce the number of osteoclasts, so as to prevent osteoporosis.

Advance of peptide-based therapeutics in migraine disease

Migraine is a periodic neurological disorder in which patients often experience unilateral, throbbing recurring headaches accompanied by nausea, vomiting, light sensitivity, sound sensitivity, and other symptoms that last from hours to days. Migraine seriously reduces the quality of life and work of patients, and it even has a significant economic and social impact. The International Headache Society categorizes migraine into three types: migraine without aura, migraine with aura and chronic migraine. 553 Migraine without aura is the most common type, accounting for 70 to 90 percent of cases.

Treatment of migraine includes medication and non-medication. For acute migraine, medication is the main treatment. Commonly used medications include painkillers, tricyclic antidepressants, calcium channel blockers, etc., which are used to relieve headaches and control the frequency of attacks. Despite the wide range of medications available, their efficacy is not satisfactory, and many others are difficult for patients to adhere to because of side effects. This is related to the fact that the exact cause of migraine is still not fully understood. In recent years, clinical models have identified key signaling molecules involved in migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide 38 (PACAP-38), and nitric oxide, whose exposure significantly increases the risk of migraine attacks. Among these molecules, calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that plays a crucial role in the pathophysiology of migraine and is a promising target for migraine therapy. 554

Monoclonal antibodies targeting CGRP have demonstrated migraine prevention in multiple Phase II and Phase III clinical trials, and their long-term effects in key regions provide stable CGRP blockade beyond existing prevention methods. Monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) and its receptor have opened a new era in migraine prevention. 555

We refer to those that antagonize CGRP receptors as gepants, which have a strong affinity for CGRP receptors and can prevent other molecules from binding to them, blocking signaling. The advantage over other types of drugs is that they do not constrict blood vessels. 556 Early studies of generation gepants relieved migraine symptoms, although their preventive effect on the disease has yet to be studied. However, development of the first generation of gepants has also been halted for various reasons, such as the discontinuation of ocegepant due to low oral bioavailability, and the banning of tecapant telcagepant and MK-3207 due to hepatotoxicity after frequent use. 557 , 558

Despite these safety concerns in the initial studies of first-generation gepants, the efficacy of gepants has prompted further efforts to develop safe CGRP-blocking molecules. Three second-generation gepants continue to be in clinical development: Rimegepant, Ubrogepant, and Atogepant. Rimegepant passed the clinical phase 2b trial based on its superior efficacy in treating acute migraine. This was followed by a Phase 3 trial ( NCT02867709 , NCT02828020 ), which was randomized, double-blind and placebo-controlled, which provided preliminary evidence of the findings of Phase IIb trial. 559 In addition, safety studies were conducted concurrently. In the Phase 2b/3 study of atogepant, the drug was also found to reduce the number of migraine days per month in patients compared to placebo. 560

In December 2019, the U.S. Food and Drug Administration, approved the first gepant drug, ubrogepant (Ubrelvy ® ), for the acute treatment of migraine in adults. Aquipta ® (atogepant) was approved by the EMA in August 2023. It is also the first and only once-daily oral calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) therapy in the European Union for the prophylactic treatment of chronic and episodic migraine. As an oral small molecule CGRP receptor antagonist, it is competitive, highly selective, and highly effective. In addition, atogepant not only prevents vasodilation, but also relieves or prevents migraine by preventing CGRP-induced neurogenic inflammation, injurious transmission, and various functions of CGRP. In a phase 3 double-blind trial, researchers randomly assigned adults with 4-14 migraine days per month in a 1:1:1:1 ratio to receive either a once-daily oral antimigraine agent (10 mg, 30 mg, or 60 mg) or a placebo for 12 weeks, 561 and the data demonstrated that the combination of the agent taken orally once daily was effective in reducing the number of migraine days and headache days. 562

Launched in September 2022, Nurtec ODT ® (rimegepant) is approved in several countries, including the US and the EU, for the acute treatment of migraine with or without aura in adults and the prophylactic treatment of episodic migraine in adults. Structurally, it contains a cyclohepta[b]pyridine core, and due to the poor water solubility of the pre-developed BMS-846372 ( < 2 μg/mL), the team fitted Rimegepant with a primary amine, which resulted in a better potency and greatly increased water solubility of this drug (50 μg/mL). In vitro, Rimegepant effectively antagonized both the CGRP receptor and the insulin 1 (AMY 1) receptor, but was about 30 times more effective at blocking the CGRP receptor. 563 It is effective not only for acute migraine, 564 , 565 but also for prophylactic treatment. 566

Launched in March 2023, zavegepant is a third-generation small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist developed by Pfizer Roots for the prevention and treatment of chronic and episodic migraine. It is the first nasal CGRP antagonist.

By comprehensively analyzing journals and patents, the researchers summarized the common structural features of CGRP receptor antagonists and synthesized the new compound. Although this molecule effectively inhibited CYP3A4, it had poor solubility. A SAR study of the side chain of benzothiophene identified 7-methylindazole as capable of enhancing activity and moderately inhibiting CYP3A4. By adding a fluorine atom at the C-8 position of the quinazolinone, the molecule BMS-694153 was synthesized, which showed a substantial increase in solubility, but low oral bioavailability. The researchers replaced the oxidation-sensitive benzylidene methylene group with an electron-deficient sp2 hypomethyl group. At the same time, a simple SAR of the piperidinopiperidine side chain to N-methylpiperidinyl-piperazine (with two protonatable nitrogens) yielded BMS-742413 (i.e., the marketed drug zavegepant), with a polar surface area of 116.18 Å2, which further reduced binding to serum proteins. In addition, the crystalline compound was surprisingly water-soluble, sufficient to support nasal administration of the drug ultimately developing zavegepant.

Several randomized, double-blind controlled trials have shown that zavegepant (Zavzpret @ ) is effective in the treatment of acute migraine with or without aura. For example, one clinical study found that a significantly higher percentage of patients in the zavegepant (Zavzpret @ ) group experienced relief from the worst symptoms of headache and MBS 2 hours after taking the drug compared to the placebo group. Specific data showed that headache relief was 23.6% in the zavegepant group compared to 14.9% in the placebo group, and MBS relief was 39.6% in the zavegepant group compared to 31.1% in the placebo group. In addition, 12.4% of patients in the zavegepant group continued to feel pain relief 48 hours after taking the drug, compared with only 8.7% in the placebo group. These studies provide ample evidence for the use of zavegepant as an effective anti-migraine therapy. 567

Advance of peptide-based vaccines

Overview of peptide-based vaccines

Since the 18th century, from the eradication of smallpox to the current global COVID-19 pandemic, vaccines have played a critical role in protecting humans and livestock from infectious diseases. 568

Through ongoing research into immune mechanisms and advancements in vaccine delivery technologies, there are currently six categories of vaccines in use or under development 569 : live attenuated vaccines, inactivated vaccines, subunit vaccines, toxoid vaccines, viral vector-based vaccines, and nucleic acid (DNA or RNA) vaccines. Traditional vaccines typically contain either live attenuated or inactivated bacteria. 570 Live attenuated vaccines and inactivated vaccines directly replicate natural infection to elicit host immunity. However, they pose risks such as the reversion of vaccine strains, potential issues with protein expression, contamination during the expression process, difficulties in pathogen cultivation, and the risk of inducing autoimmunity and excessive inflammatory responses in humans. 571 Additionally, diseases with complicated immune evasion mechanisms, such as malignancies and CMV infections, pose challenges for the production of standard attenuated live or inactivated vaccines. 572 – 575

In the field of subunit vaccines, subunits encompass membranes, capsules, toxins, polysaccharides, proteins, or small peptides. Here, our discussion of peptide-based vaccines refers to subunit-based peptide vaccines. 576 , 577 The peptides utilized in these vaccines may originate from tumor antigens or may be synthetic peptides designed to mimic them. 578 Peptide-based strategies employ minimal epitopes, providing an opportunity to select pathogen-specific protective sequences that do not cross-react with human tissues. 3 This makes peptide vaccines an attractive approach in vaccine development. Peptides have a defined chemical structure and simple construction, ensuring safety and reproducibility since they do not require folding into a tertiary structure. The ability to lyophilize and store peptide vaccines in solid form at room temperature further distinguishes them from other vaccine types. Additionally, peptide vaccines can be specifically modified to reduce the risk of adverse reactions and side effects. 579 The key features of peptide vaccines are as follows 580 – 582 : (1) precise characterization, allowing for quality control comparable to small molecule drugs; (2) lack of pathogenic sequences, lowering the risk of allergies or autoimmune reactions; (3) customization and synthesis of specific epitopes as needed 583 ; and (4) low production costs and controllable processes, facilitating commercialization. Certainly, like other vaccines, peptide vaccines also have some limitations, such as the potential for immune escape and low immunogenicity in single-peptide vaccines. 584 However, the continuous advancements in new technologies and discoveries bring new hope for the development of improved and optimized clinically effective peptide vaccines in the future.

Peptide-based vaccines have multiple design processes and corresponding mechanisms for generating an immune response (Fig. 11 ). The initiation of the immune response begins with dendritic cells (DCs) as the first step: DCs incorporated as part of the therapeutic vaccine take up exogenous antigens and differentiate into mature immunogenic DCs (Fig. 11a ). The second step involves the activation of specific T-cell responses: in lymphoid organs, peptide-loaded DCs induce specific T-cell responses (Fig. 11b ). Finally, these activated T cells migrate to the target site and exert their effects (Fig. 11c ). Currently, no peptide-based vaccines have been approved for market use. Table 7 presents the clinical trial status of peptide vaccines. Of the 16 peptide vaccines in Phase III clinical trials, only 2 are for treating immune diseases (IR-902 (NeuroVax), CV-MG01 (Myasterix)). The remaining vaccines are anticancer vaccines targeting hormone refractory prostate cancer, melanoma/metastatic cancer, acute myeloid leukemia, among others. It is clear that cancer is a prominent research area for peptide vaccines. The selection of antigens, as well as the choice of adjuvants and delivery systems, are crucial for translating peptide vaccines from the laboratory to the clinic. This paper focuses on the research progress of tumor peptide vaccines and their delivery methods. Fig. 11 The design process of peptide-based vaccines and their mechanisms for generating immune responses. a Schematic diagram of peptide-based vaccine design; ( b ) The process of causing an immune response; ( c ) Entry of peptide-based vaccines through the MHC l or MHC ll pathway Table 7 Peptide-based vaccines in clinical trial phase III No. Clinical Trial ID Name Targets 1 NCT02057159 IR-902 815 (NeuroVax) Forkhead Box P3 (FOXP3) 2 JPRN-jRCT2080222153 ITK-1 816 NA 3 NCT00094653 MDX-1379 817 HLA-A2 4 NCT04229979 galinpepimut-S 818 Wilms Tumor1 (WT1) 5 NCT05155254 IO-102/IO-103 819 Indoleamine-Pyrrole 2,3 Dioxygenase (IDO) 6 NCT05232916 GLSI-100 820 Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) 7 JPRN-UMIN000016954 Asudemotide 821 (S-588410) NA 8 NCT03200821 G17DT Immunogen(Insegia) 822 NA 9 NCT01479244 nelipepimut-s 823 (NeuVax) Human Epidermal Growth Factor Receptor 2 (HER2) 10 NCT02049151 tecemotide 824 NA 11 JPRN-UMIN000007279 OCV-C01 825 NA 12 NCT03165435 CV-MG01 826 (Myasterix) NA

Peptide-based anti-tumor vaccines

Tumor cells or lysates contain a variety of endogenous components and malignant chemicals, making them unsuitable for standard paradigms such as attenuated or inactivated vaccines. Instead, tumor-specific antigens must be screened and identified before being biologically engineered into recombinant proteins or other specialized vaccinations. Peptide vaccines based on specific epitopes are a promising strategy in oncology. 582 Tumor immunotherapy has become the fourth clinical therapeutic option for cancer, following surgery, chemotherapy, and radiation therapy. 585 Tumor vaccines work by stimulating the body’s immune system to attack and remove tumor cells. 586 In 2010, Sipuleucel-T, the first dendritic cell-based tumor vaccine, was approved by the FDA for the treatment of prostate cancer. 587 Later, various tumor vaccines have been tested in clinical trials, such as dendritic cell (DC) vaccines, gene vaccines (RNA/DNA), and peptide-based vaccinations. 586 , 588

Peptide-based tumor vaccines offer a safe and precise therapeutic strategy to cancer treatment. Within the body, they are captured, internalized, and processed by antigen-presenting cells (APCs), activating immune responses via both classical and non-classical HLA-mediated pathways. The first peptide vaccination for melanoma treatment began clinical trials in 1995, 589 targeting the MAGE-1 antigen using a nine-peptide sequence (EADPTGHSY). When APCs collect antigens, HLA presents them to MAGE-1-positive T cells, triggering an immunological response against melanoma. Unfortunately, there have been no Phase III trials reported. Optimal antigen selection is critical for the success of peptide vaccines. Ideal antigens should have tumor specificity and be easily recognized by T cells to stimulate immune responses. Tumor antigens primarily fall into three categories: tumor-associated antigens (TAAs) (overexpressed in tumor cells, low expression in normal tissue), cancer/testis antigens (CTAs) (expressed in tumors and testes), and neoantigens such as tumor-specific antigens (TSAs). 590 The first melanoma peptide targeted the cancer/testis antigen (CTA) is MAGE-1. A list of antigens that are currently in phase III clinical trials for peptide targeting is presented (Table 7 ), and to maintain objectivity and balance, we have excluded trials with undisclosed data from this list. The current Phase III clinical trial antigens mainly include HLA-A2 (single antigen, NCT00094653 ), Wilms Tumor1 (single antigen, NCT04229979 ), and Indoleamine-Pyrrole 2. Three clinical trials are currently ongoing: NCT05155254 for 3 Dioxygenase (multiple antigens), NCT05232916 for Granulocyte-Macrophage Colony-Stimulating Factor (single antigen), and NCT01479244 for Human Epidermal Growth Factor Receptor 2 (HER2) (single antigen). TAAs are also expressed in normal tissues. Under immune surveillance, the restriction of specific high-affinity T cell clones can lead to immune tolerance or provoke strong autoimmunity. This warrants discussion regarding the less-than-ideal outcomes in clinical trials, as highlighted in the article “Antitumor Peptide-Based Vaccine in the Limelight”. The emergence of TSAs brings new hope. TSAs are expressed exclusively in tumor cells and not in normal cells. They are not subject to immune tolerance restrictions, which can induce robust immune responses. TSAs originate from cancer-associated viruses, such as HPV and HBV, or mutated proteins in tumor cells. Clinical trials are underway for HPV vaccines alone or in combination with ICB. 591 – 594 Tumor progression results from dysregulated mutations in oncogenes and tumor suppressor genes. 595 – 598 These mutations, which include individual point mutations and gene rearrangements, as well as shared mutations across multiple tumors (such as EGFRvIII), provide opportunities for customizing TSAs. 593 Additionally, post-translational modifications can enrich the TSA repertoire, such as phosphorylation, lactylation, and glycosylation. 599 , 600 Compared to peptide vaccines targeting TAA, TSA vaccines offer superior immunogenicity, but their translation remains a challenge. First, antigen detection and determination are time-consuming and labor-intensive. 601 Currently, protein elution from human leukocyte antigen combined with peptide identification by mass spectrometry is used. However, advances in whole exome sequencing and bioinformatics have been used to identify individual mutations, predict novel antigens and their peptide ligands, and assess peptide-HLA affinity. 602 – 605 Since TSA arise from mutation-prone tumors, they are prone to secondary mutations during treatment and face the risk of antigen loss, 606 which means that peptide vaccines may offer a promising solution. For example, a patient with metastatic castration-sensitive prostate cancer was treated with an HLA I and HLA II-matched peptide vaccine, resulting in robust and durable CD4+ and CD8 + T cell responses. 607 Marquez-Manriquez and colleagues predicted and designed a twelve-peptide vaccine against six recurrent proteins in epithelial ovarian cancer (EOC) patients that stimulated T-cell responses and effectively prevented patient relapse, 608 greatly increasing researchers’ confidence. Peptide vaccines can activate multiple T-cell responses to avoid immune evasion, while in combination with other direct cytotoxic strategies, they can promote additional antigen spreading, amplify sustained and robust immune responses, enhance therapeutic efficacy and prevent immune suppression. 609 – 611

Clinical success of peptide-based tumor vaccines depends on adjuvants. Exceptional immunostimulants and ideal delivery strategies are critical to the ultimate clinical translation of peptide-based vaccines. Adjuvants and delivery systems intersect in vaccine development, serving the common functions of protecting peptide vaccines from degradation, assisting in peptide delivery to APCs, promoting their maturation to activate immune responses, and accelerating effector T cell homing to target sites. Traditional adjuvants such as incomplete Freund’s adjuvant (IFA) have limited ability to activate immune responses, with an objective response rate of only 2.6% (440 patients). 612 Immunostimulants currently approved for clinical use include aluminum salts (such as aluminum hydroxide and aluminum phosphate), MF59 (an oil-in-water emulsion adjuvant), AS04 (an adjuvant containing aluminum salt and monophosphoryl lipid A), CpG 1018, 613 – 616 and others. Research on novel immunostimulants continues, exploring avenues such as viral vectors, TLR4 agonists and various new materials. 588 , 617 , 618 A continued deepening of the understanding of immune response mechanisms, supported by new technologies and materials, will facilitate the transition of peptide-based vaccines from the laboratory to the clinic.

The cutting-edge technological landscape of peptide drugs

Display library technology

Display library technology is a high-throughput biological technique that is primarily used to rapidly screen for peptides or antibodies that have affinity for specific targets or antigens. The basic principle of display library technology is to construct a large library containing many different peptide or antibody sequences. These sequences are typically designed randomly to cover the possible combination space. The encoding sequences (DNA or mRNA) for each peptide or antibody molecule are connected to their surface display. This library is then incubated with the target antigen or molecule of interest. Peptides or antibodies with affinity will bind specifically to the target. The bound peptides or antibodies can then be separated out, and the sequences of the binding molecules obtained by analyzing their connected encoding sequences. Based on the screening results, key sequences or motifs of the binding peptides or antibodies can be identified. 47 , 619 , 620 Overall, display library technology can efficiently screen for peptides or antibodies with specific binding to a given target from a huge sequence library within a short time frame. This greatly shortens the traditional biological screening process and has important application value in drug development and biological detection reagents.

Currently reported peptide display library technologies mainly include phage display technology, bacterial display technologies, yeast display technologies, mammalian cell display technologies, and cell-free display technologies. 619 These technologies all utilize biological macromolecules (proteins, DNA, RNA, etc.) to display peptide sequences on surfaces, rapidly obtaining peptides with affinity for specific targets, greatly facilitates identification of original peptides for a wider range of targets.

Phage display

Phage display technology is an important peptide screening platform, first developed by Smith et al. in 1985, and now widely used for the discovery of peptides related to various diseases. 621 This technology utilizes phage libraries displaying random or designed peptide libraries on their surfaces, and screens through repetitive “biopanning” processes to obtain peptide sequences with high affinity for the target molecule. 622 The “biopanning” process includes incubating the phage library with the target molecule, washing, eluting, and amplifying bound phages. After multiple rounds of panning, phage clones with higher binding affinity for the target can be enriched. 619 , 623 Due to its unique advantages, phage display has become a preferred platform for discovering many disease-related targeting peptides, and plays an important role in cancer, 624 – 626 inflammation, 627 , 628 brain diseases, 629 , 630 blood diseases, 631 and other research fields.

As early as 2009, a bicyclic peptide-based phage display strategy was developed. Bicyclic peptides have a unique structure stabilized into bicyclic form by chemical scaffolds, avoiding reaction with phage cysteines. 632 Up to now, a number of peptides and antibodies produced by in vitro phage display are either authorized or in advanced phases of clinical development. 633 Nowadays, in vitro phage display techniques have advanced. For instance, Hampton et al. constructed bicyclic peptide phage display libraries using highly selective biparatopic reagents, and used them to screen new SARS-CoV-2 inhibitors. 634 Subsequent studies showed bicyclic peptides can be used to construct high-capacity phage libraries to combine innovative inhibition mechanisms, providing new modalities for antiviral drugs. 635 In addition, recent studies constructed bicyclic peptide libraries with stereochemical diversity, and identified a set of novel bicyclic peptides with submicromolar MYC binding affinities, validating their bioactivities in human cancer cells. 636 Nevertheless, traditional in vitro methods fall short in increasingly demanding scenarios when the goal is to produce best-in-class compounds against challenging targets. 637 To meet clinical demands, in vivo phage display, where screening is performed in living organisms, has become increasingly popular. Compared to in vitro screening, in vivo screening can select candidate peptides with desired specificities, pharmacokinetics, and stability in complex biological environments, greatly improving the possibility of screening high-affinity peptides under physiologically relevant conditions. 637 For example, LIU et al. used phage display technology combined with a novel biological screening program to obtain a peptide CLP002 (WHRSYYTWNLNT) that specifically binds to the residues of PD-L1 and PD-1 interaction and blocks the interaction of PD-1/PD-L1 in tumor cells. 638 Similarly, an EGFR specific binding peptide GE11 (YHWYGYTPQNVI) from a phage display peptide library was reported, which competitively inhibits the binding of endogenous growth factors. 639 Besides, da Fonseca Alves et al. developed a new type of electrochemical biosensor using phage display technology by screening for specific recombinant peptides to successfully distinguish serum samples from breast cancer patients and benign breast disease patients. 640 In addition, Kim et al. used the phage display peptide library Ph.D.-12 to screen out a targeting peptide PA2 that specifically binds to the outer membrane protein OprF of Pseudomonas aeruginosa. They constructed a hybrid peptide GNU7-PA2 with the antimicrobial peptide GNU7, which showed effective antimicrobial activity against P. aeruginosa without toxicity to the host. 641 The specific peptides screened out by phage display technology can be used not only therapeutically but also for diagnosis. For instance, the MAK30 peptide can serve as a probe to detect bacterial resistance to bacitracin by binding to the innovative phage display APBA-dimer library APBA-dynamic covalent warheads. This rapid and accurate detection method helps timely assess bacterial resistance and provide more precise medication guidance in clinics. 628

Bacterial display

Bacterial display is a technique that utilizes bacterial cell surfaces to present peptide libraries. Common carrier strains include Gram-negative bacteria such as E. coli and Pseudomonas. 642 Specifically, the gene encoding the peptide sequence is fused to a gene encoding a bacterial surface protein (e.g. LamB, OmpA). 643 The fusion protein expressing the peptide is then displayed on the bacterial surface. Screening against targets of interest can identify peptides with binding affinity. 644 Bacterial display has broad applications in screening antibody epitopes, receptor peptides, enzyme substrates, etc. It can also be used for protein engineering, vaccine development, biosensing and other areas. 645 Recently, the archaeal peptide display system (RAD display) has been used to screen neutralizing peptides against SARS-CoV-2 antigens, demonstrating important application prospects in the design of antigens for peptide-based vaccines. 646 Compared with phage display, advantages of bacterial display include easier operation, faster speed and lower cost. However, as the carrier is a prokaryotic organism, the displayed peptides are limited to bacterial surface expression, restricting further functional verification. In addition, low display efficiency also limits its application. 647 It is worth noting that there have been recent reports of using epPCR and single-cell sorting to rapidly enhance bacterial surface display. 648

Yeast display

Yeast display technology utilizes the cell surface of yeast to present peptide libraries. The commonly used yeast includes Pichia pastoris, Saccharomyces cerevisiae, etc. 619 The method is to fuse the gene encoding the peptide sequence to the gene encoding the yeast surface protein (e.g. Aga2p) and express the fusion protein. Then the library is screened against the target to obtain peptides with affinity. 649 , 650 Saccharomyces cerevisiae display technology, the most frequently used yeast display technology, has been utilized to map antibody-binding sites, design ideal interfaces between proteins, and evolve novel enzymes. 651 , 652 A promising method was recently reported for preparing an oral vaccine against H7N9 influenza in which the hemagglutinin (HA) of A/Anhui/1/2013 (AH-H7N9) was utilized as a model antigen and displayed on the surface of the Saccharomyces cerevisiae EBY 100. 653

Human yeast display technology is another emerging platform using humanized yeasts to present human-derived peptides and proteins, holds great potential. Many human genes encoding proteins can successfully replace the corresponding genes in yeast without compromising growth, enabling this controllable system. 654 With benefits like high transformation efficiency, large library capacity, and biosafety, human yeast display allows measuring human protein activities in a simplified organismal environment. Thus, it overcomes the limitations of immunogenicity associated with non-human display systems and facilitates discovering new human biology. 654 , 655 An illustration of this field is a platform utilizes humanized yeast display technology to express human MHC molecules on the yeast surface, which enables rapid and accurate screening of MHC-restricted T cell epitope peptides from emerging pathogens. The efficient and accurate identification of DR4 ligands from the SARS-COV-2 spike protein as a model antigen demonstrates the high efficiency and accuracy of this method. 656 In a recent update, a method called “peptide display” has been reported, in which a second-generation yeast display approach to assess peptide-MHC class II binding was developed. The method decouples peptide and MHC-II expression by displaying a peptide library on the yeast surface while expressing MHC-II proteins as soluble recombinant molecules, successfully eliminating the need for yeast-specific MHC optimization and increasing the scale of MHC-II alleles that can be utilized in yeast display screening. 657 Generally, yeast display allows detection of protein folding and post-translational modifications. However, it is relatively low throughput. Human yeast display overcomes immune compatibility issues, while retaining advantages like eukaryotic folding. But the technology is still in its early stages.

Mammalian cell display

Mammalian cell display utilizes the cell surface of mammalian cells like HEK293, CHO, etc. to present peptide libraries. 658 The method is to fuse the gene encoding the peptide with a transmembrane protein gene (e.g. PDGFR) and transfect mammalian cells to express the fusion protein on the cell surface. 659 .Mammalian cell display is especially suitable for designing humanized antibodies, studying protein-protein interactions, and developing vaccines. 660 Taking HEK293 cell display as an example, it has been applied to select antibody fragments, identify novel B cell epitopes, and engineer proteins. 661 Besides, a CHO cell line platform suitable for mammalian cell display generated by integrating a Bxb1 landing pad into a commercially available Flp-In CHO host has been recently reported. This platform has been validated for generating antibody display libraries containing up to tens of millions of variants and differentiating antibodies based on biophysical properties through mutagenesis and selection. 662 In contrast, advantages of mammalian cell display include high diversity libraries and mammalian-derived peptides, but the transfection efficiency is lower.

Cell-free display

Cell-free display technologies do not rely on living cells as carriers; instead, the peptide or protein library is linked to a genetic molecule like mRNA or cDNA, which acts as both the genotype and phenotype. In vitro transcription and translation are used to synthesize the peptide and form the linkage with the genotype without using living cells. Common techniques include ribosome display, mRNA display, cDNA display, and CIS display. 663 Ribosome display utilizes stabilized ribosome-mRNA-polypeptide complexes to display peptides. During reverse transcription, the mRNA is held on the ribosome to form a peptide-mRNA complex. 664 The most recent report of this is the use of ribosome display using rolling circle amplification to create homologous multivalent libraries to screen for low-affinity protein binders. 665 mRNA display works by covalently linking a peptide and its corresponding mRNA to form a peptide-mRNA complex that allows screening for peptides with specific properties by affinity selection. For example, by combining co- and post-translational library diversification strategies, a circulating library with reactive dehydroalanine (Dhas) was created to screen for valent cyclic peptide inhibitors in mRNA display. 666 Similarly, cDNA display forms peptide-cDNA complexes by linking peptides and their corresponding cDNA during reverse transcription and PCR to screen peptides. Recently, a customized human fetal brain cDNA phage display library was reported, and four maternal antibodies against the UH-ASD antigen were successfully screened, providing a new tool for the diagnosis of autism spectrum disorder (ASD). 667 Besides, there is also CIS display technology that enables directly connected DNA templates and the development of peptides, greatly simplifying and extending the selection process. The fundamental idea of this technology is that it makes use of the DNA replication initiation protein’s (RepA) cis-activity, which allows it to attach its own DNA template with specificity. 663 An earlier application of this method was to screen VEGFR-2 binding agents, 668 but there have been rare reports in recent years.

Overall, the primary constraint on all cell-based display technologies we mentioned above is library size, which influences the toxicity of displayed molecules to host cells as well as the effectiveness of DNA transformation. Amplification bias also affects cell display investigations, whereby little changes in growth rate can have a major effect on the total variety of the library and result in the loss of some affinity molecules when transformation. 619 Cell-free display technologies have significant advantages in this regard, advantages of which include direct genotype-phenotype linkage, large library size, no transformation limitation, and ability to use unnatural amino acids. 619 , 663 However, in vitro protein synthesis can be inefficient. There are also challenges in library construction, genotype-phenotype stability, and quantitative screening. But cell-free systems continue to be improved for peptide engineering applications.

Outlook

Moving forward, augmenting efficacy and overcoming size constraints will be key goals for phage and bacterial display systems. For yeast and mammalian cell display, increasing screening throughput is paramount. Optimizing genotype-phenotype stability and quantitative screening will drive innovation in cell-free display. As these technologies continue to progress, their capacity for engineering novel peptides and proteins will expand. By leveraging the strengths of each approach, display platforms hold great promise in generating new biological discoveries.

Application of deep learning in peptide discovery and modification

Peptide research, encompassing the study of short chains of amino acids, holds immense therapeutic potential due to the ability of these biologically active molecules to precisely target specific sites within the body. 2 , 669 However, the discovery and development of novel peptide drugs has historically been a challenging and time-consuming process. 670

The advent of techniques like deep learning (DL) has revolutionized this landscape by providing innovative tools to accelerate and enhance peptide drug design. 671 – 673 By analyzing vast datasets, these models can rapidly identify promising peptide candidates and predict optimal amino acid sequences and structures for desired therapeutic properties (Fig. 12 ). 671 , 674 The integration of DL with peptide research has led to a synergistic approach that transforms the drug discovery process through computational methodologies. 675 These platforms utilizing convolutional neural networks, recurrent neural networks, attention mechanisms and other algorithms can guide peptide synthesis for increased efficiency, 676 – 678 facilitate rational modifications to enhance bioavailability and therapeutic effects, and expedite the exploration of more possibilities with therapeutic peptides. 679 , 680 Fig. 12 A flowchart depicting the application of deep learning in peptide drug design

Application of deep learning in peptide research

The biological activities of peptides are intrinsically tied to their structural properties, hence, elucidating peptide structures and designing novel peptides is therefore critical for understanding biological mechanisms and developing new therapeutics. 670 , 681 Traditionally, techniques like molecular docking and molecular dynamics have been used to predict peptide structures by posing the problem as an energy minimization. 682 However, these methods are computationally demanding, exhibit limited accuracy, and require experimental validation. 683 To tackle these long-standing challenges, DL models can predict peptide structures and design novel peptides with higher throughput and accuracy compared to traditional techniques. 671 , 676 Application of DL in the synthesis and design of peptides mainly includes de novo peptide generation and targeted-based peptide binder design.

De novo peptide generation

In de novo peptide generation, models like Recurrent Neural Networks (RNN), 684 Long Short-Term Memory (LSTM) networks, 685 Variational Autoencoders (VAE), 686 and Generative Adversarial Networks (GAN) 687 are trained on existing peptide data. They discern intricate patterns within sequences, with a focus on generating new peptide sequences during design. There are two main methods for de novo peptide generation: sequence-based approaches and structure and sequence-based approaches. In the field of sequence-based approaches, models such as RNN 684 and LSTM 685 networks are employed. These models treat peptide design as a translation task, using neural language models to generate novel amino acid sequences or map source peptides to target peptides. Structure and sequence-based approaches integrate sequence and structural information, which significantly enhances peptide design, imbuing peptides with specific structural characteristics that contribute to their functionality and offering more effective peptide generation. In this field, models like GANDALF and HelixGAN have been reported, adeptly merging textual sequence information with structural details. 688 Advanced techniques like Wasserstein bidirectional GANs generate structurally plausible full-atom helical structures was also reported.

Targeted-based peptide binder design

Designing peptide binders that target specific proteins or biomolecules is another essential tactic for creating peptides capable of modulating key interactions. Usually known as targeted-based peptide binder design, this method also involves two primary strategies involved: de novo design and known motif-based design. 676 De novo design predicts interaction patterns and affinities between peptides and target proteins, effectively deducing amino acid sequences compatible with desired functionality and structure to discover new peptides. 689 Using AlphaFold to create de novo design models of novel macrocyclic peptides is a typical example of this method. In contrast, motif-based design relies on existing research data, incorporating key motifs from known peptide sequences or structures to bolster binding affinity. 690 The most noteworthy progress in this area is the newly described strategy for creating peptides that bind to certain locations on target proteins’ surfaces devoid of any information. 691

Future perspectives and conclusion

In summary, advances in computing power, data, and algorithms have set the stage for DL to revolutionize peptide research. Demonstrated successes in accelerating tasks like synthesis and bioactivity prediction underscore its capacity, while the growing integration of artificial intelligence into pharmaceutical workflows exemplifies accelerating adoption of these techniques. 692 – 694 As demand rises for novel peptide therapeutics, the field faces both challenges and promising solutions. 695 To step forward, integrating big data and advancements in DL is indispensable for accelerated drug design. In detail, constructing large benchmark datasets for training, along with independent validation sets, is critical to enhance reliability and aid experimentalists; incorporating structural or evolutionary information can also improve model robustness. 696 , 697 Besides, exploring nuanced sequence representations and descriptors presents opportunities for developing architectures tailored for peptides, which could improve model accuracy. 676 , 698 Looking forward, advances in computing are enabling techniques like deep learning to accelerate and empower peptide discovery. The synergy between biology and data science promises to overcome challenges and realize the full potential of peptide therapeutics.

The current status and progress of oral peptide drug delivery technologies

Though peptide drugs are widely employed in the treatment of various diseases, 2 the administration of peptide drugs has always faced enormous challenges, mainly in the following aspects: 1) Biological barriers such as pH changes in the gastrointestinal tract, degradation by proteolytic enzymes, obstruction by intestinal epithelial cells, and the first-pass effect, which make it difficult for peptide drugs to be administered orally. 699 2) Inherent physicochemical defects such as short half-lives and poor stability, which require peptide drugs to be injected multiple times a day to maintain therapeutic levels, causing inconvenience and suffering to patients. 700 3) Limitations of mucosal administration such as poor tissue permeability (hydrophilicity), enzymatic activity of mucosal macrophages, and rapid clearance in the nasal and respiratory tracts, resulting in very low bioavailability of peptide drugs administered via the mucosal route. 701 4) Risks of interactions such as immunogenicity, increased in vivo toxicity or reduced efficacy, which affect the safety and efficacy of peptide drugs. These challenges severely hamper the oral administration of peptide drugs. 702 Therefore, parenteral administration is currently the most commonly used route of administration, with subcutaneous injection being the most widely used.

In order to overcome the challenges of administering peptide drugs, researchers have been exploring novel drug delivery systems and technologies while optimizing subcutaneous administration, and have achieved rapid developments especially in the field of oral delivery. These novel drug delivery systems and technologies can not only improve the in vivo stability and bioavailability of peptide drugs, but also achieve sustained or controlled release to significantly enhance their therapeutic effects. We will first review the current status of subcutaneous administration, and then focus on the latest research progress in the development of oral peptide drugs (Table 8 ). Table 8 Approved oral peptide drugs and their oral delivery strategies Peptide Name Company Indication Strategy Approval Cyclosporin A Neoral® Novartis Pharma AG Immunosuppression after organ transplantation Lipid-based microemulsion containing lipids, surfactant, and co-solvent 1997 Sandimmune® 1990 Desmopressin acetate DDAVP® Ferring Pharmaceuticals SA Diabetes insipidus Chemical modification cyclization 1978 Voclosporin Lupkynis® Aurinia Pharmaceuticals Inc. Systemic lupus erythematosus nephritis 2021 Octeotide Mycapssa® Chiasma Inc. Acromegaly Oily suspension 2020 Semaglutide Rybelsus® Novo Nordisk Pharma AG T2DM SNAC as absorption enhancer 2019

6.3.1. Subcutaneous administration

As of 2021, five GLP-1 RAs and one insulin analog have been commercialized for subcutaneous delivery systems. Although these drugs have achieved significant effects in diabetes management, their dosages are limited by subcutaneous delivery, and injection site reactions are common adverse effects of GLP-1 RAs (especially Bydureon). Therefore, many researchers are devoted to developing and improving novel subcutaneous formulations to extend drug circulation time, increase drug safety, improve patient compliance, enable the possibility of self-administration at home, thereby reducing medical costs. 703 In 2018, the Subcutaneous Drug Delivery and Development Consortium was established, pointing out several major challenges facing optimization of subcutaneous delivery of biotherapeutics, including the need for technological innovations to achieve delivery of high-dose/volume formulations, addressing the insufficient bioavailability of subcutaneous formulations, and eliminating concerns over the higher immunogenicity of the subcutaneous route compared to the intravenous route. 704 Currently, research on subcutaneous delivery systems is mainly focused on polymeric micro/nanosystems, in situ hydrogels/fibers, ultrasound-triggered systems, etc. 705 Studies have shown that polymeric micro/nanosystems based on FDA-approved poly (lactic-co-glycolic acid) (PLGA), poly (lactic acid) (PLA) or chitosan have commercialization advantages. Through structural modifications, they can not only construct sustained/controlled release systems to improve bioavailability, but also act as vaccine adjuvants to enhance efficacy. 706

In situ hydrogels/fibers have environment-sensitive and molecule-responsive characteristics, and good biocompatibility, which are a promising alternative to traditional subcutaneous delivery systems. 707 The application of innovative materials can effectively improve the bioavailability of peptide drugs. Through structural modifications that impart glucose-responsive capabilities, controlled release of insulin can be achieved, avoiding side effects like hypoglycemia. 708 Unlike systems relying on endogenous stimuli such as pH and glucose levels, ultrasound-triggered systems are controlled by exogenous active signals to release drugs on demand. Unlike endogenous passive responses, ultrasound-responsive insulin release systems have the features of being active, visualizable, precise, and providing sustained release. A single injection can effectively control blood sugar for up to 3 days. Such systems have gradually become a hot research direction in subcutaneous delivery. 709 , 710

Oral administration

Due to the ease of degradation, poor absorption, and low bioavailability of peptide drugs in the gastrointestinal tract, frequent subcutaneous injections or other invasive administration methods are required, which brings inconvenience and suffering to patients. Therefore, the development of safe, effective and convenient oral peptide drugs has always been a hot research topic in the pharmaceutical field. 711

However, oral delivery of peptide drugs has always been an enormous challenge. In order to achieve oral delivery of peptide drugs, researchers have to overcome various biochemical and physical barriers in the gastrointestinal tract (Fig. 13 ). Firstly, peptide drugs encounter digestion by enzymes in the oral cavity, stomach and intestines, which break down the peptides into smaller molecules, resulting in loss or reduction of their activity, requiring frequent administration. Secondly, peptide drugs have to penetrate the mucus layer covering the intestinal epithelium, which is a physical barrier, as its negative charge and glycoprotein components impede drug permeation. 712 Thirdly, peptide drugs have to pass through the tight junctions between epithelial cells, which is also a physical barrier, as they restrict paracellular or transcellular permeation of drugs. Finally, after entering intestinal cells, peptide drugs may still be metabolized by cytochrome P450 enzymes or pumped out by P-glycoproteins, thus reducing their bioavailability. 713 To address these challenges in oral delivery of peptide drugs, protect them from destruction in the GI tract, increase their intestinal absorption and bioavailability, and prolong their in vivo half-life, the current mainstream strategies include structural modification and pharmaceutical formulation improvements. Fig. 13 The barriers to the oral absorption of peptide drugs mainly include biochemical and physical barriers. Initially, the physiological conditions of the gastrointestinal system led to the degradation of peptide medicines, rendering them challenging to absorb. Besides, a highly complex mucus layer covering the surface of the gastrointestinal system will considerably inhibit the absorption of peptide medicines. Figure 13 was created with biorender.com

In the field of structural modification, the methods attempted so far cover D-amino acid substitution, 714 lipidization, 50 , 231 cationization, 715 , 716 PEGylation, 717 cyclization etc., 718 , 719 which help improve the stability and permeability of peptide drugs. For example, by substituting the 8th L-arginine with D-arginine and removing the amino group from the first amino acid, an orally available desmopressin acetate (DdavpR) was successfully obtained. In addition, PEGylation and cyclization have received much attention in recent years. Conjugating PEG covalently to a drug can increase its solubility, reduce immunogenicity, prolong circulation time in vivo, thereby improving bioavailability. This method has been widely used in polypeptide and protein drugs, especially for oral delivery. For example, the PEGylated insulin analogue Tregopil developed by Indian company Biocon has completed phase III clinical trials. Recently, it was reported that surface modification of reverse micelle lipid nanocapsules (RM-LNC) with DSPE-PEG-FA (FA-RM-LNC) can increase the mucus permeability and intestinal absorption of exenatide, significantly improving its absorption efficiency in the small intestine. 720 In addition, cyclization can improve the oral absorption and stability of peptides by adding a fatty acid chain linker to the C-terminus of the peptide chain. Among the marketed oral peptides, three are cyclic peptides – cyclosporine A, voclosporin and desmopressin. The most well-known cyclic undecapeptide cyclosporine A (CsA) capsule formulation (SandimmuneR) was approved by the FDA in 1990, with an oral bioavailability as high as 25-30%. 721 In January 2021, the trans-isomer analog of CsA called voclosporin (LupkynisR) was also approved for marketing for the treatment of lupus nephritis. Recently, an interesting de novo design approach combining computational design and experimental characterization for membrane-permeable and orally bioavailable peptides has been reported. 722

In terms of pharmaceutical formulations, various pharmaceutical formulation improvement strategies including enhancing drug stability, promoting mucus permeation or adhesion, increasing epithelial permeability, carrier-mediated transport, designing sustained and controlled release formulations, and developing targeted delivery systems have also made significant progress. Some technologies have been successfully applied to marketed oral products. Strategies such as enteric coating, enzyme inhibition, 723 permeation enhancement, 724 , 725 and composite mixtures of hydrogels, 726 , 727 show promise for enabling oral delivery of other peptide drugs like exenatide and insulin. Some of these formulations are currently undergoing clinical trials. 728 Among them, the most noteworthy strategy so far is co-formulating peptides with permeation enhancers to achieve oral delivery. 58 , 724 , 729 For example, the stability and absorption of semaglutide (Rybelsus®) and somatropin through cell membranes were improved after oral co-formulation with C18 fatty acid or the chemical sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC). 730 In addition, an oral capsule formulation of octreotide containing medium chain fatty acid salts and polyvinylpyrrolidone (PVP) as suspending agents has also been achieved. It was also reported that a tricyclic peptide targeting PCSK9 (a key regulator of plasma LDL-cholesterol) attained 2.9% oral bioavailability in cynomolgus monkeys when co-administered with permeation enhancers. 731 Besides, some other peptide drugs are also exploring the potential for oral delivery through technologies such as micro/nanotechnology, targeted delivery systems, and physical devices. For example, Nicholas J. Hunt et al. reported insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer, achieving dual pH/glucose responsive oral delivery of insulin for sustained and controlled release. Results showed that the insulin distributed to the liver in animals and dose-dependently reduced blood glucose without hypoglycemia or weight gain and adverse effects in mice, rats and non-human primates. 732 Additionally, some physical devices like microneedles, patches and iontophoresis/ultrasound have also been investigated for oral delivery of peptides, piercing or stimulating the oral cavity or intestine to increase local absorption. These devices can utilize biodegradable materials such as polylactic acid, chitosan and gelatin to avoid issues with retention and removal. The advantages of microneedles and patches are reduced systemic exposure and adverse effects of peptides, but there are also some challenges like complex manufacturing, size limitations, and ensuring stability. Iontophoresis/ultrasound physically increases intestinal permeability through electric fields or sound waves, and can be co-administered with peptide drugs to enhance their intestinal absorption. The advantage of this non-invasive method is oral delivery, but its safety and tolerance to the intestine needs to be considered. 733

In summary, oral delivery of peptide drugs is a field with enormous potential and challenges that involves interdisciplinary crossover and integration, requiring continuous innovation and optimization. With the development of new materials, technologies and methods, more breakthroughs and progress will be made in oral peptide drug research, providing better options and solutions for treating various diseases. According to a recent report by Allied Market Research, the global oral polypeptide drugs market is projected to grow from USD 643 million in 2016 to USD 8.23 billion in 2028, displaying tremendous market demand and business value. It should also be noted that various administration routes including delivery to the lungs, 734 placenta, targeted nose-to-brain or intranasal, 735 transdermal diffusion, 736 and delivery to the eyes 737 are also being explored. We look forward to more peptide drugs making the journey from laboratory to clinic, clinic to market, and market to patients sooner rather than later, making contributions to human health and well-being.

Conclusion and perspective

Peptides, with their unique properties, have emerged as a prominent force in innovative drug development. Since the introduction of insulin to the market in 1922, the past two decades have witnessed the approval of nearly a hundred peptide-based drugs for treating conditions such as diabetes, obesity, and cardiovascular diseases. Beyond the well-known insulin and GLP-1 RAs, peptide drugs have also found success in treating rare diseases, exemplified by the approvals of therapies for conditions like acromegaly and hypoparathyroidism. However, most peptide drugs, barring a few exceptions like cyclosporin A, are limited by inherent drawbacks such as in vivo instability and poor bioavailability, confining their administration routes to subcutaneous injection. The recent approvals of oral semaglutide and oral insulin by the Chinese regulatory authority offer renewed hope, underscoring the potential of novel delivery technologies and innovative chemical strategies to bridge the gap between laboratory and bedside.

Transcending their therapeutic applications, peptide-based drugs have also garnered significant attention in drug delivery, vaccine development, and disease diagnostics, with approved diagnostics for conditions like Alzheimer’s disease and certain cancers. Several peptide-based drug conjugates are currently in clinical trials, and various peptide-based vaccines are undergoing Phase III clinical trials, demonstrating their transformative potential. Aided by technologies such as displ ay library screening, efficient and cost-effective synthesis, and the integration of computational biology and artificial intelligence, the discovery of novel peptide drugs, including peptide-drug complexes, new vaccines, and innovative diagnostic reagents, is accelerating. Moreover, a deep understanding of disease pathology and the microenvironment is essential for the rational design of peptide-related drugs, which may enable personalized and precise treatment for individuals.

While challenges undoubtedly lie ahead, we firmly believe that peptides will become a vital branch of innovative pharmaceuticals and biomedical research in the new era. We eagerly anticipate the next generation of peptide drugs and vaccines that will profoundly impact modern medicine, driven by the collective efforts of researchers, clinicians, and industry partners.

These authors contributed equally: Wenjing Xiao, Wenjie Jiang, Zheng Chen, Yu Huang

Acknowledgements

This work was supported by the Natural Science Foundation of China (No. 82073311), Science & Technology Department of Sichuan Province Individualized Drug Therapy Small Molecule Innovative Drugs Sichuan Youth Science and Technology Innovation Research Team (No. 2022JDTD0025), Sichuan Traditional Chinese Medicine Administration (No. 2023MS026).

Author contributions

J.Y.S.: conception and design of this work; W.J.X., W.J.J.: preparation and writing of manuscript; Z.C., Y.H.: interpretation and preparation of figures and tables, J.Y.M., W.Z.: data collection and analyze. Y.H.H.: review & editing the manuscript. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

References

1. de Leiva-Hidalgo A de Leiva-Pérez A Experiences of First Insulin-Treated Patients (1922–1923) Am. J. Ther. 2020 27 e13 e23 10.1097/MJT.0000000000001069 31876562 de Leiva-Hidalgo, A. & de Leiva-Pérez, A. Experiences of First Insulin-Treated Patients (1922–1923). Am. J. Ther. 27 , e13–e23 (2020). 31876562 10.1097/MJT.0000000000001069

2. Wang L Therapeutic peptides: current applications and future directions Signal Transduct. Tar. 2022 7 48 10.1038/s41392-022-00904-4 PMC8844085 35165272 Wang, L. et al. Therapeutic peptides: current applications and future directions. Signal Transduct. Tar. 7 , 48 (2022). 10.1038/s41392-022-00904-4 PMC8844085 35165272

3. Fosgerau K Hoffmann T Peptide therapeutics: current status and future directions Drug Discov. Today 2015 20 122 128 10.1016/j.drudis.2014.10.003 25450771 Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20 , 122–128 (2015). 25450771 10.1016/j.drudis.2014.10.003

4. Kang SJ Park SJ Mishig-Ochir T Lee BJ Antimicrobial peptides: therapeutic potentials Expert Rev. Anti Infect. Ther. 2014 12 1477 1486 10.1586/14787210.2014.976613 25371141 Kang, S. J., Park, S. J., Mishig-Ochir, T. & Lee, B. J. Antimicrobial peptides: therapeutic potentials. Expert Rev. Anti Infect. Ther. 12 , 1477–1486 (2014). 25371141 10.1586/14787210.2014.976613

5. de Oliveira AN Soares AM Da Silva SL Why to Study Peptides from Venomous and Poisonous Animals? Int. J. Pept. Res. Ther. 2023 29 76 10.1007/s10989-023-10543-0 de Oliveira, A. N., Soares, A. M. & Da Silva, S. L. Why to Study Peptides from Venomous and Poisonous Animals? Int. J. Pept. Res. Ther. 29 , 76 (2023).

6. Davidson MB Bate G Kirkpatrick P Exenatide Nat. Rev. Drug Discov. 2005 4 713 714 10.1038/nrd1828 16178120 Davidson, M. B., Bate, G. & Kirkpatrick, P. Exenatide. Nat. Rev. Drug Discov. 4 , 713–714 (2005). 16178120 10.1038/nrd1828

7. McGivern JG Ziconotide: a review of its pharmacology and use in the treatment of pain Neuropsychiatr. Dis. Treat. 2007 3 69 85 10.2147/nedt.2007.3.1.69 19300539 PMC2654521 McGivern, J. G. Ziconotide: a review of its pharmacology and use in the treatment of pain. Neuropsychiatr. Dis. Treat. 3 , 69–85 (2007). 19300539 10.2147/nedt.2007.3.1.69 PMC2654521

8. Gong J Tirofiban for acute ischemic stroke: systematic review and meta-analysis Eur. J. Clin. Pharmacol. 2020 76 475 481 10.1007/s00228-019-02817-8 31900544 Gong, J. et al. Tirofiban for acute ischemic stroke: systematic review and meta-analysis. Eur. J. Clin. Pharmacol. 76 , 475–481 (2020). 31900544 10.1007/s00228-019-02817-8

9. Tonin G Klen J Eptifibatide, an Older Therapeutic Peptide with New Indications: From Clinical Pharmacology to Everyday Clinical Practice Int. J. Mol. Sci. 2023 24 5446 10.3390/ijms24065446 36982519 PMC10049647 Tonin, G. & Klen, J. Eptifibatide, an Older Therapeutic Peptide with New Indications: From Clinical Pharmacology to Everyday Clinical Practice. Int. J. Mol. Sci. 24 , 5446 (2023). 36982519 10.3390/ijms24065446 PMC10049647

10. Lau JL Dunn MK Therapeutic peptides: Historical perspectives, current development trends, and future directions Biorg. Med. Chem. 2018 26 2700 2707 10.1016/j.bmc.2017.06.052 28720325 Lau, J. L. & Dunn, M. K. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Biorg. Med. Chem. 26 , 2700–2707 (2018). 10.1016/j.bmc.2017.06.052 28720325

11. Vigneaud VD The synthesis of an octapeptide amide with the hormonal activity of oxytocin J. Am. Chem. Soc. 1953 75 4879 4880 10.1021/ja01115a553 Vigneaud, V. D. et al. The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J. Am. Chem. Soc. 75 , 4879–4880 (1953).

12. Du Vigneaud V Gish DT Katsoyannis PG Hess GP Synthesis of the Pressor-Antidiuretic Hormone, Arginine-Vasopressin J. Am. Chem. Soc. 1958 80 3355 3358 10.1021/ja01546a040 Du Vigneaud, V., Gish, D. T., Katsoyannis, P. G. & Hess, G. P. Synthesis of the Pressor-Antidiuretic Hormone, Arginine-Vasopressin. J. Am. Chem. Soc. 80 , 3355–3358 (1958).

13. Henninot A Collins JC Nuss JM The Current State of Peptide Drug Discovery: Back to the Future? J. Med. Chem. 2018 61 1382 1414 10.1021/acs.jmedchem.7b00318 28737935 Henninot, A., Collins, J. C. & Nuss, J. M. The Current State of Peptide Drug Discovery: Back to the Future? J. Med. Chem. 61 , 1382–1414 (2018). 28737935 10.1021/acs.jmedchem.7b00318

14. Bolla M Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin N. Engl. J. Med. 1997 337 295 300 10.1056/NEJM199707313370502 9233866 Bolla, M. et al. Improved Survival in Patients with Locally Advanced Prostate Cancer Treated with Radiotherapy and Goserelin. N. Engl. J. Med. 337 , 295–300 (1997). 9233866 10.1056/NEJM199707313370502

15. Muttenthaler M King GF Adams DJ Alewood PF Trends in peptide drug discovery Nat. Rev. Drug Discov. 2021 20 309 325 10.1038/s41573-020-00135-8 33536635 Muttenthaler, M., King, G. F., Adams, D. J. & Alewood, P. F. Trends in peptide drug discovery. Nat. Rev. Drug Discov. 20 , 309–325 (2021). 33536635 10.1038/s41573-020-00135-8

16. Furusawa S Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study) Diabetes Obes. Metab. 2024 26 961 970 10.1111/dom.15393 38073422 Furusawa, S. et al. Glycaemic control efficacy of switching from dipeptidyl peptidase-4 inhibitors to oral semaglutide in subjects with type 2 diabetes: A multicentre, prospective, randomized, open-label, parallel-group comparison study (SWITCH-SEMA 2 study). Diabetes Obes. Metab. 26 , 961–970 (2024). 38073422 10.1111/dom.15393

17. Qin W Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial Diabetes Obes. Metab. 2024 26 911 923 10.1111/dom.15386 38016699 Qin, W. et al. Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial. Diabetes Obes. Metab. 26 , 911–923 (2024). 38016699 10.1111/dom.15386

18. France NL Syed YY Tirzepatide: A Review in Type 2 Diabetes Drugs 2024 84 227 238 10.1007/s40265-023-01992-4 38388874 France, N. L. & Syed, Y. Y. Tirzepatide: A Review in Type 2 Diabetes. Drugs 84 , 227–238 (2024). 38388874 10.1007/s40265-023-01992-4

19. Kaur M Misra S A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity Eur. J. Clin. Pharmacol. 2024 80 669 676 10.1007/s00228-024-03646-0 38367045 Kaur, M. & Misra, S. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. Eur. J. Clin. Pharmacol. 80 , 669–676 (2024). 38367045 10.1007/s00228-024-03646-0

20. Vahidfar N Diagnostic Value of Radiolabelled Somatostatin Analogues for Neuroendocrine Tumour Diagnosis: The Benefits and Drawbacks of [(64)Cu]Cu-DOTA-TOC Cancers (Basel) 2022 14 1914 10.3390/cancers14081914 35454822 PMC9027354 Vahidfar, N. et al. Diagnostic Value of Radiolabelled Somatostatin Analogues for Neuroendocrine Tumour Diagnosis: The Benefits and Drawbacks of [(64)Cu]Cu-DOTA-TOC. Cancers (Basel) 14 , 1914 (2022). 35454822 10.3390/cancers14081914 PMC9027354

21. Gontsarik M Yaghmur A Salentinig S Dispersed liquid crystals as pH-adjustable antimicrobial peptide nanocarriers J. Colloid Interface Sci. 2021 583 672 682 10.1016/j.jcis.2020.09.081 33039864 Gontsarik, M., Yaghmur, A. & Salentinig, S. Dispersed liquid crystals as pH-adjustable antimicrobial peptide nanocarriers. J. Colloid Interface Sci. 583 , 672–682 (2021). 33039864 10.1016/j.jcis.2020.09.081

22. Liu M Fang X Yang Y Wang C Peptide-Enabled Targeted Delivery Systems for Therapeutic Applications Front Bioeng. Biotechnol. 2021 9 701504 10.3389/fbioe.2021.701504 34277592 PMC8281044 Liu, M., Fang, X., Yang, Y. & Wang, C. Peptide-Enabled Targeted Delivery Systems for Therapeutic Applications. Front Bioeng. Biotechnol. 9 , 701504 (2021). 34277592 10.3389/fbioe.2021.701504 PMC8281044

23. McNamara K Tofail SAM Nanoparticles in biomedical applications Adv. Phys.: X. 2017 2 54 88 McNamara, K. & Tofail, S. A. M. Nanoparticles in biomedical applications. Adv. Phys.: X. 2 , 54–88 (2017). 10.1039/c5cp00831j 26024211

24. Han X Xu K Taratula O Farsad K Applications of nanoparticles in biomedical imaging Nanoscale 2019 11 799 819 10.1039/C8NR07769J 30603750 PMC8112886 Han, X., Xu, K., Taratula, O. & Farsad, K. Applications of nanoparticles in biomedical imaging. Nanoscale 11 , 799–819 (2019). 30603750 10.1039/c8nr07769j PMC8112886

25. Deng X Discovery of novel cell-penetrating and tumor-targeting peptide-drug conjugate (PDC) for programmable delivery of paclitaxel and cancer treatment Eur. J. Med. Chem. 2021 213 113050 10.1016/j.ejmech.2020.113050 33280896 Deng, X. et al. Discovery of novel cell-penetrating and tumor-targeting peptide-drug conjugate (PDC) for programmable delivery of paclitaxel and cancer treatment. Eur. J. Med. Chem. 213 , 113050 (2021). 33280896 10.1016/j.ejmech.2020.113050

26. Vyas D Patel M Wairkar S Strategies for active tumor targeting-an update Eur. J. Pharmacol. 2022 915 174512 10.1016/j.ejphar.2021.174512 34555395 Vyas, D., Patel, M. & Wairkar, S. Strategies for active tumor targeting-an update. Eur. J. Pharmacol. 915 , 174512 (2022). 34555395 10.1016/j.ejphar.2021.174512

27. Cooper BM Peptides as a platform for targeted therapeutics for cancer: Peptide–drug conjugates (PDCs) Chem. Soc. Rev. 2021 50 1480 1494 10.1039/D0CS00556H 33346298 Cooper, B. M. et al. Peptides as a platform for targeted therapeutics for cancer: Peptide–drug conjugates (PDCs). Chem. Soc. Rev. 50 , 1480–1494 (2021). 33346298 10.1039/d0cs00556h

28. Hou Y Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies Acta Pharm. Sin. B. 2023 13 3321 3338 10.1016/j.apsb.2023.01.006 37655334 PMC10465871 Hou, Y. et al. Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies. Acta Pharm. Sin. B. 13 , 3321–3338 (2023). 37655334 10.1016/j.apsb.2023.01.006 PMC10465871

29. Mathieu C The Health Economics of Automated Insulin Delivery Systems and the Potential Use of Time in Range in Diabetes Modeling: A Narrative Review Diabetes Technol. Ther. 2024 26 66 75 10.1089/dia.2023.0438 38377319 Mathieu, C. et al. The Health Economics of Automated Insulin Delivery Systems and the Potential Use of Time in Range in Diabetes Modeling: A Narrative Review. Diabetes Technol. Ther. 26 , 66–75 (2024). 38377319 10.1089/dia.2023.0438

30. Allard C Cota D Quarta C Poly-Agonist Pharmacotherapies for Metabolic Diseases: Hopes and New Challenges Drugs 2023 84 127 148 10.1007/s40265-023-01982-6 38127286 Allard, C., Cota, D. & Quarta, C. Poly-Agonist Pharmacotherapies for Metabolic Diseases: Hopes and New Challenges. Drugs 84 , 127–148 (2023). 38127286 10.1007/s40265-023-01982-6

31. Westwell-Roper C Verchere CB Modulation of Innate Immunity by Amyloidogenic Peptides Trends Immunol. 2019 40 762 780 10.1016/j.it.2019.06.005 31320280 Westwell-Roper, C. & Verchere, C. B. Modulation of Innate Immunity by Amyloidogenic Peptides. Trends Immunol. 40 , 762–780 (2019). 31320280 10.1016/j.it.2019.06.005

32. Sinner MP Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides Curr. Biol. 2021 31 564 577 10.1016/j.cub.2020.10.076 33259791 Sinner, M. P. et al. Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides. Curr. Biol. 31 , 564–577 (2021). 33259791 10.1016/j.cub.2020.10.076

33. Graeff FG Joca S Zangrossi H Jr Bradykinin actions in the central nervous system: historical overview and psychiatric implications Acta Neuropsychiatr. 2024 36 129 138 10.1017/neu.2023.57 38178717 Graeff, F. G., Joca, S. & Zangrossi, H. Jr Bradykinin actions in the central nervous system: historical overview and psychiatric implications. Acta Neuropsychiatr. 36 , 129–138 (2024). 38178717 10.1017/neu.2023.57

34. Tang M The progress of peptide vaccine clinical trials in gynecologic oncology Hum. Vaccin. Immunother. 2022 18 2062982 10.1080/21645515.2022.2062982 35687860 PMC9450897 Tang, M. et al. The progress of peptide vaccine clinical trials in gynecologic oncology. Hum. Vaccin. Immunother. 18 , 2062982 (2022). 35687860 10.1080/21645515.2022.2062982 PMC9450897

35. Li CM Novel Peptide Therapeutic Approaches for Cancer Treatment Cells 2021 10 2908 10.3390/cells10112908 34831131 PMC8616177 Li, C. M. et al. Novel Peptide Therapeutic Approaches for Cancer Treatment. Cells 10 , 2908 (2021). 34831131 10.3390/cells10112908 PMC8616177

36. Vadevoo SMP Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy Arch. Pharm. Res. 2019 42 150 158 10.1007/s12272-019-01125-0 30756310 Vadevoo, S. M. P. et al. Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy. Arch. Pharm. Res. 42 , 150–158 (2019). 30756310 10.1007/s12272-019-01125-0

37. McGregor DP Discovering and improving novel peptide therapeutics Curr. Opin. Pharmacol. 2008 8 616 619 10.1016/j.coph.2008.06.002 18602024 McGregor, D. P. Discovering and improving novel peptide therapeutics. Curr. Opin. Pharmacol. 8 , 616–619 (2008). 18602024 10.1016/j.coph.2008.06.002

38. Behrendt R White P Offer J Advances in Fmoc solid-phase peptide synthesis J. Pept. Sci. 2016 22 4 27 10.1002/psc.2836 26785684 PMC4745034 Behrendt, R., White, P. & Offer, J. Advances in Fmoc solid-phase peptide synthesis. J. Pept. Sci. 22 , 4–27 (2016). 26785684 10.1002/psc.2836 PMC4745034

39. Amblard M Fehrentz JA Martinez J Subra G Methods and protocols of modern solid phase Peptide synthesis Mol. Biotechnol. 2006 33 239 254 10.1385/MB:33:3:239 16946453 Amblard, M., Fehrentz, J. A., Martinez, J. & Subra, G. Methods and protocols of modern solid phase Peptide synthesis. Mol. Biotechnol. 33 , 239–254 (2006). 16946453 10.1385/MB:33:3:239

40. Kim H Jang JH Jung IY Cho JH A Novel Peptide as a Specific and Selective Probe for Klebsiella pneumoniae Detection Biosens. (Basel) 2022 12 153 10.3390/bios12030153 PMC8946155 35323423 Kim, H., Jang, J. H., Jung, I. Y. & Cho, J. H. A Novel Peptide as a Specific and Selective Probe for Klebsiella pneumoniae Detection. Biosens. (Basel) 12 , 153 (2022). 10.3390/bios12030153 PMC8946155 35323423

41. Ladner RC Sato AK Gorzelany J de Souza M Phage display-derived peptides as therapeutic alternatives to antibodies Drug Discov. Today 2004 9 525 529 10.1016/S1359-6446(04)03104-6 15183160 Ladner, R. C., Sato, A. K., Gorzelany, J. & de Souza, M. Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov. Today 9 , 525–529 (2004). 15183160 10.1016/S1359-6446(04)03104-6

42. Aloisio A Phage-Displayed Peptides for Targeting Tyrosine Kinase Membrane Receptors in Cancer Therapy Viruses 2021 13 649 10.3390/v13040649 33918836 PMC8070105 Aloisio, A. et al. Phage-Displayed Peptides for Targeting Tyrosine Kinase Membrane Receptors in Cancer Therapy. Viruses 13 , 649 (2021). 33918836 10.3390/v13040649 PMC8070105

43. Xia J Perspectives and trends in advanced optical and electrochemical biosensors based on engineered peptides Mikrochim. Acta 2023 190 327 10.1007/s00604-023-05907-8 37495747 Xia, J. et al. Perspectives and trends in advanced optical and electrochemical biosensors based on engineered peptides. Mikrochim. Acta 190 , 327 (2023). 37495747 10.1007/s00604-023-05907-8

44. Hummel G Reineke U Reimer U Translating peptides into small molecules Mol. Biosyst. 2006 2 499 508 10.1039/b611791k 17216031 Hummel, G., Reineke, U. & Reimer, U. Translating peptides into small molecules. Mol. Biosyst. 2 , 499–508 (2006). 17216031 10.1039/b611791k

45. Loffet A Peptides as drugs: is there a market? J. Pept. Sci. 2002 8 1 7 10.1002/psc.366 11831558 Loffet, A. Peptides as drugs: is there a market? J. Pept. Sci. 8 , 1–7 (2002). 11831558 10.1002/psc.366

46. Kwon D Kim SM Correia MA Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications Acta Pharm. Sin. B 2020 10 42 60 10.1016/j.apsb.2019.11.002 31993306 PMC6976991 Kwon, D., Kim, S. M. & Correia, M. A. Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications. Acta Pharm. Sin. B 10 , 42–60 (2020). 31993306 10.1016/j.apsb.2019.11.002 PMC6976991

47. Anand U Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate Biofactors 2023 49 251 269 10.1002/biof.1913 36326181 Anand, U. et al. Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate. Biofactors 49 , 251–269 (2023). 36326181 10.1002/biof.1913

48. Smith MC Gestwicki JE Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity Expert Rev. Mol. Med. 2012 14 e16 10.1017/erm.2012.10 22831787 PMC3591511 Smith, M. C. & Gestwicki, J. E. Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev. Mol. Med. 14 , e16 (2012). 22831787 10.1017/erm.2012.10 PMC3591511

49. Lu H Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials Signal Transduct. Target Ther. 2020 5 213 10.1038/s41392-020-00315-3 32968059 PMC7511340 Lu, H. et al. Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal Transduct. Target Ther. 5 , 213 (2020). 32968059 10.1038/s41392-020-00315-3 PMC7511340

50. Haddadzadegan S Dorkoosh F Bernkop-Schnürch A Oral delivery of therapeutic peptides and proteins: Technology landscape of lipid-based nanocarriers Adv. Drug Deliv. Rev. 2022 182 114097 10.1016/j.addr.2021.114097 34999121 Haddadzadegan, S., Dorkoosh, F. & Bernkop-Schnürch, A. Oral delivery of therapeutic peptides and proteins: Technology landscape of lipid-based nanocarriers. Adv. Drug Deliv. Rev. 182 , 114097 (2022). 34999121 10.1016/j.addr.2021.114097

51. Cao SJ Nanoparticles: Oral Delivery for Protein and Peptide Drugs AAPS PharmSciTech 2019 20 190 10.1208/s12249-019-1325-z 31111296 PMC6527526 Cao, S. J. et al. Nanoparticles: Oral Delivery for Protein and Peptide Drugs. AAPS PharmSciTech 20 , 190 (2019). 31111296 10.1208/s12249-019-1325-z PMC6527526

52. Zhou X Po ALW Peptide and protein drugs: II. Non-parenteral routes of delivery Int. J. Pharm. 1991 75 117 130 10.1016/0378-5173(91)90185-Q Zhou, X. & Po, A. L. W. Peptide and protein drugs: II. Non-parenteral routes of delivery. Int. J. Pharm. 75 , 117–130 (1991).

53. Mahato RI Narang AS Thoma L Miller DD Emerging trends in oral delivery of peptide and protein drugs Crit. Rev. Ther. Drug Carr. Syst. 2003 20 153 214 10.1615/CritRevTherDrugCarrierSyst.v20.i23.30 14584523 Mahato, R. I., Narang, A. S., Thoma, L. & Miller, D. D. Emerging trends in oral delivery of peptide and protein drugs. Crit. Rev. Ther. Drug Carr. Syst. 20 , 153–214 (2003). 10.1615/critrevtherdrugcarriersyst.v20.i23.30 14584523

54. Nicze M The Current and Promising Oral Delivery Methods for Protein-and Peptide-Based Drugs Int. J. Mol. Sci. 2024 25 815 10.3390/ijms25020815 38255888 PMC10815890 Nicze, M. et al. The Current and Promising Oral Delivery Methods for Protein-and Peptide-Based Drugs. Int. J. Mol. Sci. 25 , 815 (2024). 38255888 10.3390/ijms25020815 PMC10815890

55. Jiang Y Recent advances in design of antimicrobial peptides and polypeptides toward clinical translation Adv. Drug Del. Rev. 2021 170 261 280 10.1016/j.addr.2020.12.016 33400958 Jiang, Y. et al. Recent advances in design of antimicrobial peptides and polypeptides toward clinical translation. Adv. Drug Del. Rev. 170 , 261–280 (2021). 10.1016/j.addr.2020.12.016 33400958

56. Christou GA Semaglutide as a promising antiobesity drug Obes. Rev. 2019 20 805 815 10.1111/obr.12839 30768766 Christou, G. A. et al. Semaglutide as a promising antiobesity drug. Obes. Rev. 20 , 805–815 (2019). 30768766 10.1111/obr.12839

57. Xiang C Wang Y Liu H A scientometrics review on nonpoint source pollution research Ecol. Eng. 2017 99 400 408 10.1016/j.ecoleng.2016.11.028 Xiang, C., Wang, Y. & Liu, H. A scientometrics review on nonpoint source pollution research. Ecol. Eng. 99 , 400–408 (2017).

58. Gleeson JP Fein KC Whitehead KA Oral delivery of peptide therapeutics in infants: Challenges and opportunities Adv. Drug Del. Rev. 2021 173 112 124 10.1016/j.addr.2021.03.011 PMC8178217 33774115 Gleeson, J. P., Fein, K. C. & Whitehead, K. A. Oral delivery of peptide therapeutics in infants: Challenges and opportunities. Adv. Drug Del. Rev. 173 , 112–124 (2021). 10.1016/j.addr.2021.03.011 PMC8178217 33774115

59. Ong KL Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021 Lancet 2023 402 203 234 10.1016/S0140-6736(23)01301-6 37356446 PMC10364581 Ong, K. L. et al. Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet 402 , 203–234 (2023). 37356446 10.1016/S0140-6736(23)01301-6 PMC10364581

60. Tichy EM National trends in prescription drug expenditures and projections for 2024 Am. J. Health Syst. Pharm. 2024 81 583 598 10.1093/ajhp/zxae105 38656319 Tichy, E. M. et al. National trends in prescription drug expenditures and projections for 2024. Am. J. Health Syst. Pharm. 81 , 583–598 (2024). 38656319 10.1093/ajhp/zxae105

61. Yu G Lessons and Applications of Omics Research in Diabetes Epidemiology Curr. Diab. Rep. 2024 24 27 44 10.1007/s11892-024-01533-7 38294727 PMC10874344 Yu, G. et al. Lessons and Applications of Omics Research in Diabetes Epidemiology. Curr. Diab. Rep. 24 , 27–44 (2024). 38294727 10.1007/s11892-024-01533-7 PMC10874344

62. Lim C Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis J. Mater. Chem. B 2023 11 10131 10146 10.1039/D3TB01202F 37830254 Lim, C. et al. Development and application of novel peptide-formulated nanoparticles for treatment of atopic dermatitis. J. Mater. Chem. B 11 , 10131–10146 (2023). 37830254 10.1039/d3tb01202f

63. Wang M Peptide-drug conjugates: A new paradigm for targeted cancer therapy Eur. J. Med. Chem. 2024 265 116119 10.1016/j.ejmech.2023.116119 38194773 Wang, M. et al. Peptide-drug conjugates: A new paradigm for targeted cancer therapy. Eur. J. Med. Chem. 265 , 116119 (2024). 38194773 10.1016/j.ejmech.2023.116119

64. Vysochinskaya V Cell-penetrating peptide and cationic liposomes mediated siRNA delivery to arrest growth of chronic myeloid leukemia cells in vitro Biochimie 2024 221 1 12 10.1016/j.biochi.2024.01.006 38215931 Vysochinskaya, V. et al. Cell-penetrating peptide and cationic liposomes mediated siRNA delivery to arrest growth of chronic myeloid leukemia cells in vitro. Biochimie 221 , 1–12 (2024). 38215931 10.1016/j.biochi.2024.01.006

65. Fu Z Antibody drug conjugate: the “biological missile” for targeted cancer therapy Signal Transduct. Tar. 2022 7 93 10.1038/s41392-022-00947-7 PMC8941077 35318309 Fu, Z. et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct. Tar. 7 , 93 (2022). 10.1038/s41392-022-00947-7 PMC8941077 35318309

66. Tsuchikama K Anami Y Ha SYY Yamazaki CM Exploring the next generation of antibody–drug conjugates Nat. Rev. Clin. Oncol. 2024 21 203 223 10.1038/s41571-023-00850-2 38191923 Tsuchikama, K., Anami, Y., Ha, S. Y. Y. & Yamazaki, C. M. Exploring the next generation of antibody–drug conjugates. Nat. Rev. Clin. Oncol. 21 , 203–223 (2024). 38191923 10.1038/s41571-023-00850-2

67. Fu C Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope? Acta Pharm. Sin. B. 2023 13 498 516 10.1016/j.apsb.2022.07.020 36873165 PMC9978859 Fu, C. et al. Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope? Acta Pharm. Sin. B. 13 , 498–516 (2023). 36873165 10.1016/j.apsb.2022.07.020 PMC9978859

68. Rizvi SFA Zhang L Zhang H Fang Q Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic ACS Pharmacol. Transl. Sci. 2024 7 309 334 10.1021/acsptsci.3c00269 38357281 PMC10863443 Rizvi, S. F. A., Zhang, L., Zhang, H. & Fang, Q. Peptide-Drug Conjugates: Design, Chemistry, and Drug Delivery System as a Novel Cancer Theranostic. ACS Pharmacol. Transl. Sci. 7 , 309–334 (2024). 38357281 10.1021/acsptsci.3c00269 PMC10863443

69. Cerrato CP Langel Ü An update on cell-penetrating peptides with intracellular organelle targeting Expert Opin. Drug Deliv. 2022 19 133 146 10.1080/17425247.2022.2034784 35086398 Cerrato, C. P. & Langel, Ü. An update on cell-penetrating peptides with intracellular organelle targeting. Expert Opin. Drug Deliv. 19 , 133–146 (2022). 35086398 10.1080/17425247.2022.2034784

70. Ji X Nielsen AL Heinis C Cyclic Peptides for Drug Development Angew. Chem. Int. Ed. 2024 63 e202308251 10.1002/anie.202308251 37870189 Ji, X., Nielsen, A. L. & Heinis, C. Cyclic Peptides for Drug Development. Angew. Chem. Int. Ed. 63 , e202308251 (2024). 10.1002/anie.202308251 37870189

71. Bisht T Adhikari A Patil S Dhoundiyal S Bioconjugation Techniques for Enhancing Stability and Targeting Efficiency of Protein and Peptide Therapeutics Curr. Protein Pept. Sci. 2024 25 226 243 10.2174/0113892037268777231013154850 37921168 Bisht, T., Adhikari, A., Patil, S. & Dhoundiyal, S. Bioconjugation Techniques for Enhancing Stability and Targeting Efficiency of Protein and Peptide Therapeutics. Curr. Protein Pept. Sci. 25 , 226–243 (2024). 37921168 10.2174/0113892037268777231013154850

72. Rohira H Arora A Kaur P Chugh A Peptide cargo administration: current state and applications Appl. Microbiol. Biotechnol. 2023 107 3153 3181 10.1007/s00253-023-12512-5 37052636 PMC10099029 Rohira, H., Arora, A., Kaur, P. & Chugh, A. Peptide cargo administration: current state and applications. Appl. Microbiol. Biotechnol. 107 , 3153–3181 (2023). 37052636 10.1007/s00253-023-12512-5 PMC10099029

73. Xu J Cell-penetrating peptide: a means of breaking through the physiological barriers of different tissues and organs J. Control. Release 2019 309 106 124 10.1016/j.jconrel.2019.07.020 31323244 Xu, J. et al. Cell-penetrating peptide: a means of breaking through the physiological barriers of different tissues and organs. J. Control. Release 309 , 106–124 (2019). 31323244 10.1016/j.jconrel.2019.07.020

74. Alas M Saghaeidehkordi A Kaur K Peptide–Drug Conjugates with Different Linkers for Cancer Therapy J. Med. Chem. 2021 64 216 232 10.1021/acs.jmedchem.0c01530 33382619 PMC8610607 Alas, M., Saghaeidehkordi, A. & Kaur, K. Peptide–Drug Conjugates with Different Linkers for Cancer Therapy. J. Med. Chem. 64 , 216–232 (2021). 33382619 10.1021/acs.jmedchem.0c01530 PMC8610607

75. Javid H RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions Cancer Med. 2024 13 e6800 10.1002/cam4.6800 38349028 PMC10832341 Javid, H. et al. RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions. Cancer Med. 13 , e6800 (2024). 38349028 10.1002/cam4.6800 PMC10832341

76. Tripodi AAP In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery Pathol. Oncol. Res. 2020 26 1879 1892 10.1007/s12253-019-00773-3 31820302 PMC7297862 Tripodi, A. A. P. et al. In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery. Pathol. Oncol. Res. 26 , 1879–1892 (2020). 31820302 10.1007/s12253-019-00773-3 PMC7297862

77. Sakshi S Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery Curr. Med. Chem. 2024 31 1 25 10.2174/0109298673278936240107121907 38362688 Sakshi, S. et al. Cell-Penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery. Curr. Med. Chem. 31 , 1–25 (2024). 10.2174/0109298673278936240107121907 38362688

78. Ghaemi B Cell-Penetrating and Enzyme-Responsive Peptides for Targeted Cancer Therapy: Role of Arginine Residue Length on Cell Penetration and In Vivo Systemic Toxicity ACS Appl. Mater. Interfaces 2024 16 11159 11171 10.1021/acsami.3c14908 38385360 PMC11362383 Ghaemi, B. et al. Cell-Penetrating and Enzyme-Responsive Peptides for Targeted Cancer Therapy: Role of Arginine Residue Length on Cell Penetration and In Vivo Systemic Toxicity. ACS Appl. Mater. Interfaces 16 , 11159–11171 (2024). 38385360 10.1021/acsami.3c14908 PMC11362383

79. Straubhaar J D’Souza A Niziolek Z Budnik B Single cell proteomics analysis of drug response shows its potential as a drug discovery platform Mol. Omics 2024 20 6 18 10.1039/D3MO00124E 37681418 Straubhaar, J., D’Souza, A., Niziolek, Z. & Budnik, B. Single cell proteomics analysis of drug response shows its potential as a drug discovery platform. Mol. Omics 20 , 6–18 (2024). 37681418 10.1039/d3mo00124e

80. Xu L Phage Display Screening of Anchor Peptides for Red Blood Cell-Derived Extracellular Vesicles ACS Omega 2024 9 6492 6504 10.1021/acsomega.3c06527 38371813 PMC10870408 Xu, L. et al. Phage Display Screening of Anchor Peptides for Red Blood Cell-Derived Extracellular Vesicles. ACS Omega 9 , 6492–6504 (2024). 38371813 10.1021/acsomega.3c06527 PMC10870408

81. Gong L Research advances in peptide‒drug conjugates Acta Pharm. Sin. B. 2023 13 3659 3677 10.1016/j.apsb.2023.02.013 37719380 PMC10501876 Gong, L. et al. Research advances in peptide‒drug conjugates. Acta Pharm. Sin. B. 13 , 3659–3677 (2023). 37719380 10.1016/j.apsb.2023.02.013 PMC10501876

82. Walles M Connor A Hainzl D ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development Curr. Top. Med. Chem. 2017 17 3463 3475 10.2174/1568026618666180118153502 29357804 Walles, M., Connor, A. & Hainzl, D. ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development. Curr. Top. Med. Chem. 17 , 3463–3475 (2017). 29357804 10.2174/1568026618666180118153502

83. Bargh JD Isidro-Llobet A Parker JS Spring DR Cleavable linkers in antibody–drug conjugates Chem. Soc. Rev. 2019 48 4361 4374 10.1039/C8CS00676H 31294429 Bargh, J. D., Isidro-Llobet, A., Parker, J. S. & Spring, D. R. Cleavable linkers in antibody–drug conjugates. Chem. Soc. Rev. 48 , 4361–4374 (2019). 31294429 10.1039/c8cs00676h

84. Mező G Oxime-Linked Peptide–Daunomycin Conjugates as Good Tools for Selection of Suitable Homing Devices in Targeted Tumor Therapy: An Overview Int. J. Mol. Sci. 2024 25 1864 10.3390/ijms25031864 38339141 PMC10855781 Mező, G. et al. Oxime-Linked Peptide–Daunomycin Conjugates as Good Tools for Selection of Suitable Homing Devices in Targeted Tumor Therapy: An Overview. Int. J. Mol. Sci. 25 , 1864 (2024). 38339141 10.3390/ijms25031864 PMC10855781

85. Zhou H Stimuli-responsive peptide hydrogels for biomedical applications J. Mater. Chem. B 2024 12 1748 1774 10.1039/D3TB02610H 38305498 Zhou, H. et al. Stimuli-responsive peptide hydrogels for biomedical applications. J. Mater. Chem. B 12 , 1748–1774 (2024). 38305498 10.1039/d3tb02610h

86. Yang Y Drug conjugate-based anticancer therapy - Current status and perspectives Cancer Lett. 2023 552 215969 10.1016/j.canlet.2022.215969 36279982 Yang, Y. et al. Drug conjugate-based anticancer therapy - Current status and perspectives. Cancer Lett. 552 , 215969 (2023). 36279982 10.1016/j.canlet.2022.215969

87. Vrettos EI Mező G Tzakos AG On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site Beilstein J. Org. Chem. 2018 14 930 954 10.3762/bjoc.14.80 29765474 PMC5942387 Vrettos, E. I., Mező, G. & Tzakos, A. G. On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site. Beilstein J. Org. Chem. 14 , 930–954 (2018). 29765474 10.3762/bjoc.14.80 PMC5942387

88. Stokke C Kvassheim M Blakkisrud J Radionuclides for Targeted Therapy: Physical Properties Molecules 2022 27 5429 10.3390/molecules27175429 36080198 PMC9457625 Stokke, C., Kvassheim, M. & Blakkisrud, J. Radionuclides for Targeted Therapy: Physical Properties. Molecules 27 , 5429 (2022). 36080198 10.3390/molecules27175429 PMC9457625

89. Coenen HH Ermert J Expanding PET-applications in life sciences with positron-emitters beyond fluorine-18 Nucl. Med. Biol. 2021 92 241 269 10.1016/j.nucmedbio.2020.07.003 32900582 Coenen, H. H. & Ermert, J. Expanding PET-applications in life sciences with positron-emitters beyond fluorine-18. Nucl. Med. Biol. 92 , 241–269 (2021). 32900582 10.1016/j.nucmedbio.2020.07.003

90. Yamaya T Tashima H Takyu S Takahashi M Whole Gamma Imaging: Challenges and Opportunities PET Clin. 2024 19 83 93 10.1016/j.cpet.2023.08.003 37718218 Yamaya, T., Tashima, H., Takyu, S. & Takahashi, M. Whole Gamma Imaging: Challenges and Opportunities. PET Clin. 19 , 83–93 (2024). 37718218 10.1016/j.cpet.2023.08.003

91. Hoppenz P Els-Heindl S Beck-Sickinger AG Peptide-Drug Conjugates and Their Targets in Advanced Cancer Therapies Front. Chem. 2020 8 571 10.3389/fchem.2020.00571 32733853 PMC7359416 Hoppenz, P., Els-Heindl, S. & Beck-Sickinger, A. G. Peptide-Drug Conjugates and Their Targets in Advanced Cancer Therapies. Front. Chem. 8 , 571 (2020). 32733853 10.3389/fchem.2020.00571 PMC7359416

92. Keam SJ Lutetium Lu 177 Vipivotide Tetraxetan: First Approval Mol. Diagn. Ther. 2022 26 467 475 10.1007/s40291-022-00594-2 35553387 PMC9099330 Keam, S. J. Lutetium Lu 177 Vipivotide Tetraxetan: First Approval. Mol. Diagn. Ther. 26 , 467–475 (2022). 35553387 10.1007/s40291-022-00594-2 PMC9099330

93. Jessee JK Pepaxto: A New Peptide-Drug Conjugate for Heavily Pretreated Relapsed and Refractory Multiple Myeloma Ann. Pharmacother. 2021 56 951 957 10.1177/10600280211058388 34963319 Jessee, J. K. Pepaxto: A New Peptide-Drug Conjugate for Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Ann. Pharmacother. 56 , 951–957 (2021). 34963319 10.1177/10600280211058388

94. Wu M Huang W Yang N Liu Y Learn from antibody–drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy Exp. Hematol. Oncol. 2022 11 93 10.1186/s40164-022-00347-1 36348391 PMC9644565 Wu, M., Huang, W., Yang, N. & Liu, Y. Learn from antibody–drug conjugates: consideration in the future construction of peptide-drug conjugates for cancer therapy. Exp. Hematol. Oncol. 11 , 93 (2022). 36348391 10.1186/s40164-022-00347-1 PMC9644565

95. McCurdy A Visram A The Role of Belantamab Mafodotin, Selinexor, and Melflufen in Multiple Myeloma Curr. Hematol. Malig. Rep. 2022 17 306 318 10.1007/s11899-022-00682-4 36417082 PMC9684923 McCurdy, A. & Visram, A. The Role of Belantamab Mafodotin, Selinexor, and Melflufen in Multiple Myeloma. Curr. Hematol. Malig. Rep. 17 , 306–318 (2022). 36417082 10.1007/s11899-022-00682-4 PMC9684923

96. Wang Y Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies Pharmaceutics 2024 16 240 10.3390/pharmaceutics16020240 38399294 PMC10893007 Wang, Y. et al. Peptide-Mediated Nanocarriers for Targeted Drug Delivery: Developments and Strategies. Pharmaceutics 16 , 240 (2024). 38399294 10.3390/pharmaceutics16020240 PMC10893007

97. Fodor K The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma Oncotarget 2020 11 175 10.18632/oncotarget.27431 32010430 PMC6968782 Fodor, K. et al. The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma. Oncotarget 11 , 175 (2020). 32010430 10.18632/oncotarget.27431 PMC6968782

98. Paulus J Sewald N Small molecule- and peptide-drug conjugates addressing integrins: A story of targeted cancer treatment J. Pept. Sci. 2024 30 e3561 10.1002/psc.3561 38382900 Paulus, J. & Sewald, N. Small molecule- and peptide-drug conjugates addressing integrins: A story of targeted cancer treatment. J. Pept. Sci. 30 , e3561 (2024). 38382900 10.1002/psc.3561

99. Liu F Wu Q Dong Z Liu K Integrins in cancer: Emerging mechanisms and therapeutic opportunities Pharmacol. Ther. 2023 247 108458 10.1016/j.pharmthera.2023.108458 37245545 Liu, F., Wu, Q., Dong, Z. & Liu, K. Integrins in cancer: Emerging mechanisms and therapeutic opportunities. Pharmacol. Ther. 247 , 108458 (2023). 37245545 10.1016/j.pharmthera.2023.108458

100. Cheng Y Ji Y RGD-modified polymer and liposome nanovehicles: Recent research progress for drug delivery in cancer therapeutics Eur. J. Pharm. Sci. 2019 128 8 17 10.1016/j.ejps.2018.11.023 30471410 Cheng, Y. & Ji, Y. RGD-modified polymer and liposome nanovehicles: Recent research progress for drug delivery in cancer therapeutics. Eur. J. Pharm. Sci. 128 , 8–17 (2019). 30471410 10.1016/j.ejps.2018.11.023

101. Cho YS Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer Biomaterials 2022 289 121783 10.1016/j.biomaterials.2022.121783 36084486 Cho, Y. S. et al. Sustained potentiation of bystander killing via PTEN-loss driven macropinocytosis targeted peptide-drug conjugate therapy in metastatic triple-negative breast cancer. Biomaterials 289 , 121783 (2022). 36084486 10.1016/j.biomaterials.2022.121783

102. Reader CS The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy J. Pathol. 2019 249 332 342 10.1002/path.5320 31259422 PMC6852434 Reader, C. S. et al. The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. J. Pathol. 249 , 332–342 (2019). 31259422 10.1002/path.5320 PMC6852434

103. Moore KM Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus Theranostics 2020 10 2930 10.7150/thno.38702 32194845 PMC7053198 Moore, K. M. et al. Integrin αvβ6-specific therapy for pancreatic cancer developed from foot-and-mouth-disease virus. Theranostics 10 , 2930 (2020). 32194845 10.7150/thno.38702 PMC7053198

104. Sabbah DA Hajjo R Sweidan K Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors Curr. Top. Med. Chem. 2020 20 815 834 10.2174/1568026620666200303123102 32124699 Sabbah, D. A., Hajjo, R. & Sweidan, K. Review on epidermal growth factor receptor (EGFR) structure, signaling pathways, interactions, and recent updates of EGFR inhibitors. Curr. Top. Med. Chem. 20 , 815–834 (2020). 32124699 10.2174/1568026620666200303123102

105. Yu L Synthesis and biological evaluation of phthalocyanine-peptide conjugate for EGFR-targeted photodynamic therapy and bioimaging Dyes Pigment 2019 163 197 203 10.1016/j.dyepig.2018.11.055 Yu, L. et al. Synthesis and biological evaluation of phthalocyanine-peptide conjugate for EGFR-targeted photodynamic therapy and bioimaging. Dyes Pigment 163 , 197–203 (2019).

106. Chu JCH Fong W-P Wong CTT Ng DKP Facile Synthesis of Cyclic Peptide–Phthalocyanine Conjugates for Epidermal Growth Factor Receptor-Targeted Photodynamic Therapy J. Med. Chem. 2021 64 2064 2076 10.1021/acs.jmedchem.0c01677 33577327 Chu, J. C. H., Fong, W.-P., Wong, C. T. T. & Ng, D. K. P. Facile Synthesis of Cyclic Peptide–Phthalocyanine Conjugates for Epidermal Growth Factor Receptor-Targeted Photodynamic Therapy. J. Med. Chem. 64 , 2064–2076 (2021). 33577327 10.1021/acs.jmedchem.0c01677

107. Philippe GJ-B Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a Cell-Penetrating Peptide J. Med. Chem. 2024 67 1197 1208 10.1021/acs.jmedchem.3c01682 38174919 Philippe, G. J.-B. et al. Delivery to, and Reactivation of, the p53 Pathway in Cancer Cells Using a Grafted Cyclotide Conjugated with a Cell-Penetrating Peptide. J. Med. Chem. 67 , 1197–1208 (2024). 38174919 10.1021/acs.jmedchem.3c01682

108. Galogre M A review of HER2 overexpression and somatic mutations in cancers Crit. Rev. Oncol. /Hematol. 2023 186 103997 10.1016/j.critrevonc.2023.103997 37062337 Galogre, M. et al. A review of HER2 overexpression and somatic mutations in cancers. Crit. Rev. Oncol. /Hematol. 186 , 103997 (2023). 37062337 10.1016/j.critrevonc.2023.103997

109. Liu, S., Tian, Y., Jiang, S. & Wang, Z. A Novel Homodimer Peptide–Drug Conjugate Improves the Efficacy of HER2-Positive Breast Cancer Therapy. Int. J. Mol. Sci . 24 (2023). 10.3390/ijms24054590 PMC10003747 36902021

110. Zhou J Design, synthesis and bioactivity evaluation of novel fusion peptides and their CPT conjugates inducing effective anti-tumor responses on HER2 positive tumors Eur. J. Med. Chem. 2024 264 116032 10.1016/j.ejmech.2023.116032 38104378 Zhou, J. et al. Design, synthesis and bioactivity evaluation of novel fusion peptides and their CPT conjugates inducing effective anti-tumor responses on HER2 positive tumors. Eur. J. Med. Chem. 264 , 116032 (2024). 38104378 10.1016/j.ejmech.2023.116032

111. Candelaria, P. V., Leoh, L. S., Penichet, M. L. & Daniels-Wells, T. R. Antibodies Targeting the Transferrin Receptor 1 (TfR1) as Direct Anti-cancer Agents. Front. Immunol . 12 (2021). 10.3389/fimmu.2021.607692 PMC8010148 33815364

112. Li S Design, synthesis, and in vitro antitumor activity of a transferrin receptor-targeted peptide–doxorubicin conjugate Chem. Biol. Drug Des. 2020 95 58 65 10.1111/cbdd.13613 31452330 Li, S. et al. Design, synthesis, and in vitro antitumor activity of a transferrin receptor-targeted peptide–doxorubicin conjugate. Chem. Biol. Drug Des. 95 , 58–65 (2020). 31452330 10.1111/cbdd.13613

113. Bataille Backer P Development of a Targeted SN-38-Conjugate for the Treatment of Glioblastoma ACS Omega 2024 9 2615 2628 10.1021/acsomega.3c07486 38250376 PMC10795035 Bataille Backer, P. et al. Development of a Targeted SN-38-Conjugate for the Treatment of Glioblastoma. ACS Omega 9 , 2615–2628 (2024). 38250376 10.1021/acsomega.3c07486 PMC10795035

114. Castillo-Avila RG Association between Genetic Variants of CELSR2-PSRC1-SORT1 and Cardiovascular Diseases: A Systematic Review and Meta-Analysis J. Cardiovasc. Dev. Dis. 2023 10 91 36975855 10.3390/jcdd10030091 PMC10056735 Castillo-Avila, R. G. et al. Association between Genetic Variants of CELSR2-PSRC1-SORT1 and Cardiovascular Diseases: A Systematic Review and Meta-Analysis. J. Cardiovasc. Dev. Dis. 10 , 91 (2023). 36975855 10.3390/jcdd10030091 PMC10056735

115. Demeule M TH1902, a new docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer Cancer Sci. 2021 112 4317 4334 10.1111/cas.15086 34314556 PMC8486219 Demeule, M. et al. TH1902, a new docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer. Cancer Sci. 112 , 4317–4334 (2021). 34314556 10.1111/cas.15086 PMC8486219

116. Mabeta P Steenkamp V The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy Int. J. Mol. Sci. 2022 23 15585 10.3390/ijms232415585 36555234 PMC9779738 Mabeta, P. & Steenkamp, V. The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy. Int. J. Mol. Sci. 23 , 15585 (2022). 36555234 10.3390/ijms232415585 PMC9779738

117. Wang D A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy Cell Death Discov. 2022 8 411 10.1038/s41420-022-01198-9 36202781 PMC9537177 Wang, D. et al. A VEGFR targeting peptide-drug conjugate (PDC) suppresses tumor angiogenesis in a TACE model for hepatocellular carcinoma therapy. Cell Death Discov. 8 , 411 (2022). 36202781 10.1038/s41420-022-01198-9 PMC9537177

118. Rigby M BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors Mol. Cancer Ther. 2022 21 1747 1756 10.1158/1535-7163.MCT-21-0875 36112771 PMC9940631 Rigby, M. et al. BT8009; A Nectin-4 Targeting Bicycle Toxin Conjugate for Treatment of Solid Tumors. Mol. Cancer Ther. 21 , 1747–1756 (2022). 36112771 10.1158/1535-7163.MCT-21-0875 PMC9940631

119. Gerster-Gilliéron K 90Y-DOTATOC as a therapeutic option for complex recurrent or progressive meningiomas J. Nucl. Med. 2015 56 1748 1751 10.2967/jnumed.115.155853 26294303 Gerster-Gilliéron, K. et al. 90Y-DOTATOC as a therapeutic option for complex recurrent or progressive meningiomas. J. Nucl. Med. 56 , 1748–1751 (2015). 26294303 10.2967/jnumed.115.155853

120. Jo U TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor Mol. Cancer Ther. 2022 21 1090 1102 10.1158/1535-7163.MCT-21-1000 35439320 PMC9256811 Jo, U. et al. TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor. Mol. Cancer Ther. 21 , 1090–1102 (2022). 35439320 10.1158/1535-7163.MCT-21-1000 PMC9256811

121. Fang Y Smart glypican-3-targeting peptide–chlorin e6 conjugates for targeted photodynamic therapy of hepatocellular carcinoma Eur. J. Med. Chem. 2024 264 116047 10.1016/j.ejmech.2023.116047 38118394 Fang, Y. et al. Smart glypican-3-targeting peptide–chlorin e6 conjugates for targeted photodynamic therapy of hepatocellular carcinoma. Eur. J. Med. Chem. 264 , 116047 (2024). 38118394 10.1016/j.ejmech.2023.116047

122. Rütter M E-selectin-targeted polymer-doxorubicin conjugate induces regression of established colorectal liver metastases and improves mice survival Nano Today 2024 55 102182 10.1016/j.nantod.2024.102182 Rütter, M. et al. E-selectin-targeted polymer-doxorubicin conjugate induces regression of established colorectal liver metastases and improves mice survival. Nano Today 55 , 102182 (2024).

123. Szabó I Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH–Peptide Conjugates Int. J. Mol. Sci. 2024 25 1095 10.3390/ijms25021095 38256168 PMC10816934 Szabó, I. et al. Targeting the Melanocortin 1 Receptor in Melanoma: Biological Activity of α-MSH–Peptide Conjugates. Int. J. Mol. Sci. 25 , 1095 (2024). 38256168 10.3390/ijms25021095 PMC10816934

124. Qiao JX Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1) Bioorg. Med. Chem. Lett. 2024 98 129589 10.1016/j.bmcl.2023.129589 38097140 Qiao, J. X. et al. Exploration of macrocyclic peptide binders to the extracellular CRD domain of human receptor tyrosine kinase-like orphan receptor 1 (ROR1). Bioorg. Med. Chem. Lett. 98 , 129589 (2024). 38097140 10.1016/j.bmcl.2023.129589

125. Chen X An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer Eur. J. Med. Chem. 2022 241 114617 10.1016/j.ejmech.2022.114617 35932567 Chen, X. et al. An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer. Eur. J. Med. Chem. 241 , 114617 (2022). 35932567 10.1016/j.ejmech.2022.114617

126. Jiang Y DTX-P7, a peptide–drug conjugate, is highly effective for non-small cell lung cancer J. Hematol. Oncol. 2022 15 73 10.1186/s13045-022-01274-8 35659720 PMC9164557 Jiang, Y. et al. DTX-P7, a peptide–drug conjugate, is highly effective for non-small cell lung cancer. J. Hematol. Oncol. 15 , 73 (2022). 35659720 10.1186/s13045-022-01274-8 PMC9164557

127. Dai Q Xie L Ren E Liu G Cathepsin B Responsive Peptide–Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics Nano Lett. 2024 24 950 957 10.1021/acs.nanolett.3c04371 38198622 Dai, Q., Xie, L., Ren, E. & Liu, G. Cathepsin B Responsive Peptide–Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics. Nano Lett. 24 , 950–957 (2024). 38198622 10.1021/acs.nanolett.3c04371

128. Porosk L Gaidutšik I Langel Ü Approaches for the discovery of new cell-penetrating peptides Expert Opin. Drug Dis. 2021 16 553 565 10.1080/17460441.2021.1851187 33874824 Porosk, L., Gaidutšik, I. & Langel, Ü. Approaches for the discovery of new cell-penetrating peptides. Expert Opin. Drug Dis. 16 , 553–565 (2021). 10.1080/17460441.2021.1851187 33874824

129. Hummer AM Deane CM Designing stable humanized antibodies Nat. Biomed. Eng. 2024 8 3 4 10.1038/s41551-023-01168-1 38151639 Hummer, A. M. & Deane, C. M. Designing stable humanized antibodies. Nat. Biomed. Eng. 8 , 3–4 (2024). 38151639 10.1038/s41551-023-01168-1

130. Sun T Jiang C Stimuli-responsive drug delivery systems triggered by intracellular or subcellular microenvironments Adv. Drug Del. Rev. 2023 196 114773 10.1016/j.addr.2023.114773 36906230 Sun, T. & Jiang, C. Stimuli-responsive drug delivery systems triggered by intracellular or subcellular microenvironments. Adv. Drug Del. Rev. 196 , 114773 (2023). 10.1016/j.addr.2023.114773 36906230

131. Yadav M Eswari JS Opportunistic Challenges of Computer-aided Drug Discovery of Lipopeptides: New Insights for Large Molecule Therapeutics Avicenna J. Med. Biotechnol. 2023 15 3 36789119 10.18502/ajmb.v15i1.11419 PMC9895984 Yadav, M. & Eswari, J. S. Opportunistic Challenges of Computer-aided Drug Discovery of Lipopeptides: New Insights for Large Molecule Therapeutics. Avicenna J. Med. Biotechnol. 15 , 3 (2023). 36789119 10.18502/ajmb.v15i1.11419 PMC9895984

132. Moody TW Peptide receptors as cancer drug targets Ann. N. Y. Acad. Sci. 2019 1455 141 148 10.1111/nyas.14100 31074514 PMC6834859 Moody, T. W. Peptide receptors as cancer drug targets. Ann. N. Y. Acad. Sci. 1455 , 141–148 (2019). 31074514 10.1111/nyas.14100 PMC6834859

133. Li M A composite peptide-supramolecular microneedle system for melanoma immunotherapy Nano Res. 2023 16 5335 5345 10.1007/s12274-022-5236-z Li, M. et al. A composite peptide-supramolecular microneedle system for melanoma immunotherapy. Nano Res. 16 , 5335–5345 (2023).

134. Kohn DB Chen YY Spencer MJ Successes and challenges in clinical gene therapy Gene Ther. 2023 30 738 746 10.1038/s41434-023-00390-5 37935854 PMC10678346 Kohn, D. B., Chen, Y. Y. & Spencer, M. J. Successes and challenges in clinical gene therapy. Gene Ther. 30 , 738–746 (2023). 37935854 10.1038/s41434-023-00390-5 PMC10678346

135. Akbarian M Khani A Eghbalpour S Uversky VN Bioactive Peptides: Synthesis, Sources, Applications, and Proposed Mechanisms of Action Int. J. Mol. Sci. 2022 23 1445 10.3390/ijms23031445 35163367 PMC8836030 Akbarian, M., Khani, A., Eghbalpour, S. & Uversky, V. N. Bioactive Peptides: Synthesis, Sources, Applications, and Proposed Mechanisms of Action. Int. J. Mol. Sci. 23 , 1445 (2022). 35163367 10.3390/ijms23031445 PMC8836030

136. Xu J Penetrating peptides: Applications in drug delivery J. Drug Deliv. Sci. Technol. 2023 84 104475 10.1016/j.jddst.2023.104475 Xu, J. et al. Penetrating peptides: Applications in drug delivery. J. Drug Deliv. Sci. Technol. 84 , 104475 (2023).

137. Kotadiya DD Patel P Patel HD Cell-Penetrating Peptides: A Powerful Tool for Targeted Drug Delivery Curr. Drug Deliv. 2024 21 368 388 10.2174/1567201820666230407092924 37026498 Kotadiya, D. D., Patel, P. & Patel, H. D. Cell-Penetrating Peptides: A Powerful Tool for Targeted Drug Delivery. Curr. Drug Deliv. 21 , 368–388 (2024). 37026498 10.2174/1567201820666230407092924

138. Zhang D Wang J Xu D Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems J. Control. Release 2016 229 130 139 10.1016/j.jconrel.2016.03.020 26993425 Zhang, D., Wang, J. & Xu, D. Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems. J. Control. Release 229 , 130–139 (2016). 26993425 10.1016/j.jconrel.2016.03.020

139. Frankel AD Pabo CO Cellular uptake of the tat protein from human immunodeficiency virus Cell 1988 55 1189 1193 10.1016/0092-8674(88)90263-2 2849510 Frankel, A. D. & Pabo, C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55 , 1189–1193 (1988). 2849510 10.1016/0092-8674(88)90263-2

140. Chen Y A codelivery system loaded with PDL1-siRNA and sorafenib enhances the therapeutic effect of sorafenib on hepatocellular carcinoma via TAT-poly-SS-lysine modified chitosan Int. J. Biol. Macromol. 2024 263 130162 10.1016/j.ijbiomac.2024.130162 38365149 Chen, Y. et al. A codelivery system loaded with PDL1-siRNA and sorafenib enhances the therapeutic effect of sorafenib on hepatocellular carcinoma via TAT-poly-SS-lysine modified chitosan. Int. J. Biol. Macromol. 263 , 130162 (2024). 38365149 10.1016/j.ijbiomac.2024.130162

141. Lichtenstein M TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases Life 2021 11 924 10.3390/life11090924 34575072 PMC8466028 Lichtenstein, M. et al. TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases. Life 11 , 924 (2021). 34575072 10.3390/life11090924 PMC8466028

142. Liu X Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma ACS Nano 2023 17 16432 16447 10.1021/acsnano.2c12857 37646615 PMC10510715 Liu, X. et al. Engineered Extracellular Vesicle-Delivered CRISPR/Cas9 for Radiotherapy Sensitization of Glioblastoma. ACS Nano 17 , 16432–16447 (2023). 37646615 10.1021/acsnano.2c12857 PMC10510715

143. Wan Y Fluorinated Cell-Penetrating Peptide for Co-Delivering siHIF-1α and Sorafenib to Enhance In Vitro Anti-Tumor Efficacy Pharmaceutics 2023 15 2789 10.3390/pharmaceutics15122789 38140129 PMC10747150 Wan, Y. et al. Fluorinated Cell-Penetrating Peptide for Co-Delivering siHIF-1α and Sorafenib to Enhance In Vitro Anti-Tumor Efficacy. Pharmaceutics 15 , 2789 (2023). 38140129 10.3390/pharmaceutics15122789 PMC10747150

144. Kardani K Milani A H. Shabani S Bolhassani A Cell penetrating peptides: the potent multi-cargo intracellular carriers Expert Opin. Drug Deliv. 2019 16 1227 1258 10.1080/17425247.2019.1676720 31583914 Kardani, K., Milani, A., H. Shabani, S. & Bolhassani, A. Cell penetrating peptides: the potent multi-cargo intracellular carriers. Expert Opin. Drug Deliv. 16 , 1227–1258 (2019). 31583914 10.1080/17425247.2019.1676720

145. Shoari A Tooyserkani R Tahmasebi M Löwik DWPM Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade Pharmaceutics 2021 13 1391 10.3390/pharmaceutics13091391 34575464 PMC8470549 Shoari, A., Tooyserkani, R., Tahmasebi, M. & Löwik, D. W. P. M. Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade. Pharmaceutics 13 , 1391 (2021). 34575464 10.3390/pharmaceutics13091391 PMC8470549

146. Liu Y Zhao Z Li M Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers Asian J. Pharm. Sci. 2022 17 523 543 36105313 10.1016/j.ajps.2022.05.002 PMC9458999 Liu, Y., Zhao, Z. & Li, M. Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers. Asian J. Pharm. Sci. 17 , 523–543 (2022). 36105313 10.1016/j.ajps.2022.05.002 PMC9458999

147. Tsuchiya K Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers Int. J. Mol. Sci. 2023 24 11768 10.3390/ijms241411768 37511527 PMC10380766 Tsuchiya, K. et al. Development of Hydrophobic Cell-Penetrating Stapled Peptides as Drug Carriers. Int. J. Mol. Sci. 24 , 11768 (2023). 37511527 10.3390/ijms241411768 PMC10380766

148. Ruseska I Zimmer A Internalization mechanisms of cell-penetrating peptides Beilstein J. Nanotechnol. 2020 11 101 123 10.3762/bjnano.11.10 31976201 PMC6964662 Ruseska, I. & Zimmer, A. Internalization mechanisms of cell-penetrating peptides. Beilstein J. Nanotechnol. 11 , 101–123 (2020). 31976201 10.3762/bjnano.11.10 PMC6964662

149. Huang X Li G Antimicrobial Peptides and Cell-Penetrating Peptides: Non-Antibiotic Membrane-Targeting Strategies Against Bacterial Infections Infect. Drug Resistance. 2023 16 1203 1219 10.2147/IDR.S396566 PMC9985452 36879855 Huang, X. & Li, G. Antimicrobial Peptides and Cell-Penetrating Peptides: Non-Antibiotic Membrane-Targeting Strategies Against Bacterial Infections. Infect. Drug Resistance. 16 , 1203–1219 (2023). 10.2147/IDR.S396566 PMC9985452 36879855

150. Islam MZ Sharmin S Moniruzzaman M Yamazaki M Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells Appl. Microbiol. Biotechnol. 2018 102 3879 3892 10.1007/s00253-018-8889-5 29523934 Islam, M. Z., Sharmin, S., Moniruzzaman, M. & Yamazaki, M. Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells. Appl. Microbiol. Biotechnol. 102 , 3879–3892 (2018). 29523934 10.1007/s00253-018-8889-5

151. Ruczynski J Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells Folia Histochem. Cytobiol. 2014 52 257 269 10.5603/FHC.a2014.0034 25530464 Ruczynski, J. et al. Cell-penetrating peptides as a promising tool for delivery of various molecules into the cells. Folia Histochem. Cytobiol. 52 , 257–269 (2014). 25530464 10.5603/FHC.a2014.0034

152. Hao M Zhang L Chen P Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides Int. J. Mol. Sci. 2022 23 9038 10.3390/ijms23169038 36012300 PMC9409441 Hao, M., Zhang, L. & Chen, P. Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides. Int. J. Mol. Sci. 23 , 9038 (2022). 36012300 10.3390/ijms23169038 PMC9409441

153. Kaplan IM Wadia JS Dowdy SF Cationic TAT peptide transduction domain enters cells by macropinocytosis J. Control. Release 2005 102 247 253 10.1016/j.jconrel.2004.10.018 15653149 Kaplan, I. M., Wadia, J. S. & Dowdy, S. F. Cationic TAT peptide transduction domain enters cells by macropinocytosis. J. Control. Release 102 , 247–253 (2005). 15653149 10.1016/j.jconrel.2004.10.018

154. Gollapudi S Steric pressure between glycosylated transmembrane proteins inhibits internalization by endocytosis Proc. Natl Acad. Sci. 2023 120 e2215815120 10.1073/pnas.2215815120 37023126 PMC10104535 Gollapudi, S. et al. Steric pressure between glycosylated transmembrane proteins inhibits internalization by endocytosis. Proc. Natl Acad. Sci. 120 , e2215815120 (2023). 37023126 10.1073/pnas.2215815120 PMC10104535

155. Wei T Development of oral curcumin based on pH-responsive transmembrane peptide-cyclodextrin derivative nanoparticles for hepatoma Carbohydr. Polym. 2022 277 118892 10.1016/j.carbpol.2021.118892 34893294 Wei, T. et al. Development of oral curcumin based on pH-responsive transmembrane peptide-cyclodextrin derivative nanoparticles for hepatoma. Carbohydr. Polym. 277 , 118892 (2022). 34893294 10.1016/j.carbpol.2021.118892

156. Erazo-Oliveras A Improving the Endosomal Escape of Cell-Penetrating Peptides and Their Cargos: Strategies and Challenges Pharmaceuticals 2012 5 1177 1209 10.3390/ph5111177 24223492 PMC3816665 Erazo-Oliveras, A. et al. Improving the Endosomal Escape of Cell-Penetrating Peptides and Their Cargos: Strategies and Challenges. Pharmaceuticals 5 , 1177–1209 (2012). 24223492 10.3390/ph5111177 PMC3816665

157. Davidson TA McGoldrick SJ Kohn DH Phage Display to Augment Biomaterial Function Int. J. Mol. Sci. 2020 21 5994 10.3390/ijms21175994 32825391 PMC7504225 Davidson, T. A., McGoldrick, S. J. & Kohn, D. H. Phage Display to Augment Biomaterial Function. Int. J. Mol. Sci. 21 , 5994 (2020). 32825391 10.3390/ijms21175994 PMC7504225

158. Pleiko K In vivo phage display: identification of organ-specific peptides using deep sequencing and differential profiling across tissues Nucleic Acids Res 2021 49 e38 e38 10.1093/nar/gkaa1279 33444445 PMC8053097 Pleiko, K. et al. In vivo phage display: identification of organ-specific peptides using deep sequencing and differential profiling across tissues. Nucleic Acids Res 49 , e38–e38 (2021). 33444445 10.1093/nar/gkaa1279 PMC8053097

159. Goyal R Molecular hybridization combining tumor homing and penetrating peptide domains for cellular targeting Drug Deliv. Transl. Res. 2022 12 1285 1292 10.1007/s13346-021-01035-z 34333729 Goyal, R. et al. Molecular hybridization combining tumor homing and penetrating peptide domains for cellular targeting. Drug Deliv. Transl. Res. 12 , 1285–1292 (2022). 34333729 10.1007/s13346-021-01035-z

160. Tonnelet D Angiogenesis imaging study using interim [18 F] RGD-K5 PET/CT in patients with lymphoma undergoing chemotherapy: preliminary evidence EJNMMI Res. 2021 11 1 9 10.1186/s13550-021-00776-9 33846870 PMC8041962 Tonnelet, D. et al. Angiogenesis imaging study using interim [18 F] RGD-K5 PET/CT in patients with lymphoma undergoing chemotherapy: preliminary evidence. EJNMMI Res. 11 , 1–9 (2021). 33846870 10.1186/s13550-021-00776-9 PMC8041962

161. Dahri M Nanoscale aggregation of doxorubicin-short peptide conjugates for enzyme-responsive delivery with various MOF carriers: In-silico steps towards smart cancer chemotherapy Comput. Biol. Med. 2022 144 105386 10.1016/j.compbiomed.2022.105386 35272116 Dahri, M. et al. Nanoscale aggregation of doxorubicin-short peptide conjugates for enzyme-responsive delivery with various MOF carriers: In-silico steps towards smart cancer chemotherapy. Comput. Biol. Med. 144 , 105386 (2022). 35272116 10.1016/j.compbiomed.2022.105386

162. Haddad Y Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells J. Nanobiotechnol. 2020 18 95 10.1186/s12951-020-00654-x PMC7359476 32660596 Haddad, Y. et al. Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells. J. Nanobiotechnol. 18 , 95 (2020). 10.1186/s12951-020-00654-x PMC7359476 32660596

163. Li H iRGD peptide-mediated liposomal nanoparticles with photoacoustic/ultrasound dual-modality imaging for precision theranostics against hepatocellular carcinoma Int. J. Nanomed. 2021 21 6455 6475 10.2147/IJN.S325891 PMC8464346 34584411 Li, H. et al. iRGD peptide-mediated liposomal nanoparticles with photoacoustic/ultrasound dual-modality imaging for precision theranostics against hepatocellular carcinoma. Int. J. Nanomed. 21 , 6455–6475 (2021). 10.2147/IJN.S325891 PMC8464346 34584411

164. Pal S Albumin Nanoparticles Surface Decorated with a Tumor-Homing Peptide Help in Selective Killing of Triple-Negative Breast Cancer Cells ACS Appl. Mater. Interfaces 2023 15 46721 46737 10.1021/acsami.3c11561 37756635 Pal, S. et al. Albumin Nanoparticles Surface Decorated with a Tumor-Homing Peptide Help in Selective Killing of Triple-Negative Breast Cancer Cells. ACS Appl. Mater. Interfaces 15 , 46721–46737 (2023). 37756635 10.1021/acsami.3c11561

165. Seyyednia E Nanoparticles modified with vasculature-homing peptides for targeted cancer therapy and angiogenesis imaging J. Control. Release 2021 338 367 393 10.1016/j.jconrel.2021.08.044 34461174 Seyyednia, E. et al. Nanoparticles modified with vasculature-homing peptides for targeted cancer therapy and angiogenesis imaging. J. Control. Release 338 , 367–393 (2021). 34461174 10.1016/j.jconrel.2021.08.044

166. Singh T Tumor–homing peptide iRGD-conjugate enhances tumor accumulation of camptothecin for colon cancer therapy Eur. J. Med. Chem. 2024 265 116050 10.1016/j.ejmech.2023.116050 38128233 Singh, T. et al. Tumor–homing peptide iRGD-conjugate enhances tumor accumulation of camptothecin for colon cancer therapy. Eur. J. Med. Chem. 265 , 116050 (2024). 38128233 10.1016/j.ejmech.2023.116050

167. Genta I GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview Pharmaceutics 2018 10 2 10.3390/pharmaceutics10010002 PMC5874815 29271876 Genta, I. et al. GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview. Pharmaceutics 10 , 2 (2018). 10.3390/pharmaceutics10010002 PMC5874815 29271876

168. Fotoohi-Ardakani G Targeting MCF-7 Cell Line by Listeriolysin O Pore Forming Toxin Fusion with AHNP Targeted Peptide Adv. Biomed. Res. 2019 8 33 10.4103/abr.abr_18_19 31259162 PMC6543864 Fotoohi-Ardakani, G. et al. Targeting MCF-7 Cell Line by Listeriolysin O Pore Forming Toxin Fusion with AHNP Targeted Peptide. Adv. Biomed. Res. 8 , 33 (2019). 31259162 10.4103/abr.abr_18_19 PMC6543864

169. Kang S Lee S Park S iRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery Polymers 2020 12 1906 10.3390/polym12091906 32847045 PMC7563641 Kang, S., Lee, S. & Park, S. iRGD Peptide as a Tumor-Penetrating Enhancer for Tumor-Targeted Drug Delivery. Polymers 12 , 1906 (2020). 32847045 10.3390/polym12091906 PMC7563641

170. Wu Y-J Design and characterization of a novel tumor-homing cell-penetrating peptide for drug delivery in TGFBR3 high-expressing tumors Chem. Biol. Drug Des. 2023 102 1421 1434 10.1111/cbdd.14333 37620132 Wu, Y.-J. et al. Design and characterization of a novel tumor-homing cell-penetrating peptide for drug delivery in TGFBR3 high-expressing tumors. Chem. Biol. Drug Des. 102 , 1421–1434 (2023). 37620132 10.1111/cbdd.14333

171. Kondo E Iioka H Saito K Tumor-homing peptide and its utility for advanced cancer medicine Cancer Sci. 2021 112 2118 2125 10.1111/cas.14909 33793015 PMC8177760 Kondo, E., Iioka, H. & Saito, K. Tumor-homing peptide and its utility for advanced cancer medicine. Cancer Sci. 112 , 2118–2125 (2021). 33793015 10.1111/cas.14909 PMC8177760

172. Tarvirdipour S A self-assembling peptidic platform to boost the cellular uptake and nuclear delivery of oligonucleotides Biomater. Sci. 2022 10 4309 4323 10.1039/D2BM00826B 35771211 Tarvirdipour, S. et al. A self-assembling peptidic platform to boost the cellular uptake and nuclear delivery of oligonucleotides. Biomater. Sci. 10 , 4309–4323 (2022). 35771211 10.1039/d2bm00826b

173. Zahid M Identification of a Cardiac Specific Protein Transduction Domain by In Vivo Biopanning Using a M13 Phage Peptide Display Library in Mice PLoS One 2010 5 e12252 10.1371/journal.pone.0012252 20808875 PMC2923200 Zahid, M. et al. Identification of a Cardiac Specific Protein Transduction Domain by In Vivo Biopanning Using a M13 Phage Peptide Display Library in Mice. PLoS One 5 , e12252 (2010). 20808875 10.1371/journal.pone.0012252 PMC2923200

174. Iwasaki T Murakami N Kawano T A polylysine–polyhistidine fusion peptide for lysosome-targeted protein delivery Biochem. Biophys. Res. Commun. 2020 533 905 912 10.1016/j.bbrc.2020.09.087 33008588 Iwasaki, T., Murakami, N. & Kawano, T. A polylysine–polyhistidine fusion peptide for lysosome-targeted protein delivery. Biochem. Biophys. Res. Commun. 533 , 905–912 (2020). 33008588 10.1016/j.bbrc.2020.09.087

175. Li X Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression Acta Pharm. Sin. B. 2021 11 2655 2669 10.1016/j.apsb.2021.06.010 34589387 PMC8463443 Li, X. et al. Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and MDMX for P53 activation and tumor suppression. Acta Pharm. Sin. B. 11 , 2655–2669 (2021). 34589387 10.1016/j.apsb.2021.06.010 PMC8463443

176. Panigrahi B Cyclic peptides nanospheres: A ‘2-in-1′ self-assembled delivery system for targeting nucleus and cytoplasm Eur. J. Pharm. Sci. 2022 171 106125 10.1016/j.ejps.2022.106125 35033697 Panigrahi, B. et al. Cyclic peptides nanospheres: A ‘2-in-1′ self-assembled delivery system for targeting nucleus and cytoplasm. Eur. J. Pharm. Sci. 171 , 106125 (2022). 35033697 10.1016/j.ejps.2022.106125

177. Hijová E Benefits of Biotics for Cardiovascular Diseases Int. J. Mol. Sci. 2023 24 6292 10.3390/ijms24076292 37047262 PMC10093891 Hijová, E. Benefits of Biotics for Cardiovascular Diseases. Int. J. Mol. Sci. 24 , 6292 (2023). 37047262 10.3390/ijms24076292 PMC10093891

178. Cerrato CP Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides J. Mater. Chem. B 2020 8 10825 10836 10.1039/D0TB01106A 33174901 Cerrato, C. P. et al. Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides. J. Mater. Chem. B 8 , 10825–10836 (2020). 33174901 10.1039/d0tb01106a

179. Sahagun D Zahid M Cardiac-Targeting Peptide: From Discovery to Applications Biomolecules 2023 13 1690 10.3390/biom13121690 38136562 PMC10741768 Sahagun, D. & Zahid, M. Cardiac-Targeting Peptide: From Discovery to Applications. Biomolecules 13 , 1690 (2023). 38136562 10.3390/biom13121690 PMC10741768

180. von Mentzer B A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine J. Pharm. Pharmacol. 2020 72 1352 1360 10.1111/jphp.13317 32588458 PMC7486274 von Mentzer, B. et al. A CGRP receptor antagonist peptide formulated for nasal administration to treat migraine. J. Pharm. Pharmacol. 72 , 1352–1360 (2020). 32588458 10.1111/jphp.13317 PMC7486274

181. Torchilin VP Recent approaches to intracellular delivery of drugs and DNA and organelle targeting Annu. Rev. Biomed. Eng. 2006 8 343 375 10.1146/annurev.bioeng.8.061505.095735 16834560 Torchilin, V. P. Recent approaches to intracellular delivery of drugs and DNA and organelle targeting. Annu. Rev. Biomed. Eng. 8 , 343–375 (2006). 16834560 10.1146/annurev.bioeng.8.061505.095735

182. Ahlschwede KM Cationic carrier peptide enhances cerebrovascular targeting of nanoparticles in Alzheimer’s disease brain Nanomed. Nanotechnol. Biol. Med. 2019 16 258 266 10.1016/j.nano.2018.09.010 30300748 Ahlschwede, K. M. et al. Cationic carrier peptide enhances cerebrovascular targeting of nanoparticles in Alzheimer’s disease brain. Nanomed. Nanotechnol. Biol. Med. 16 , 258–266 (2019). 10.1016/j.nano.2018.09.010 30300748

183. Mansur AAP Bioengineered Carboxymethylcellulose–Peptide Hybrid Nanozyme Cascade for Targeted Intracellular Biocatalytic–Magnetothermal Therapy of Brain Cancer Cells Pharmaceutics 2022 14 2223 10.3390/pharmaceutics14102223 36297660 PMC9611945 Mansur, A. A. P. et al. Bioengineered Carboxymethylcellulose–Peptide Hybrid Nanozyme Cascade for Targeted Intracellular Biocatalytic–Magnetothermal Therapy of Brain Cancer Cells. Pharmaceutics 14 , 2223 (2022). 36297660 10.3390/pharmaceutics14102223 PMC9611945

184. Lee MF Poh CL Strategies to improve the physicochemical properties of peptide-based drugs Pharm. Res. 2023 40 617 632 10.1007/s11095-023-03486-0 36869247 Lee, M. F. & Poh, C. L. Strategies to improve the physicochemical properties of peptide-based drugs. Pharm. Res. 40 , 617–632 (2023). 36869247 10.1007/s11095-023-03486-0

185. Pei D How Do Biomolecules Cross the Cell Membrane? Acc. Chem. Res. 2022 55 309 318 10.1021/acs.accounts.1c00560 35015508 PMC9175464 Pei, D. How Do Biomolecules Cross the Cell Membrane? Acc. Chem. Res. 55 , 309–318 (2022). 35015508 10.1021/acs.accounts.1c00560 PMC9175464

186. Sylvestre M Replacement of L-amino acid peptides with D-amino acid peptides mitigates anti-PEG antibody generation against polymer-peptide conjugates in mice J. Control. Release 2021 331 142 153 10.1016/j.jconrel.2021.01.015 33444669 PMC7946756 Sylvestre, M. et al. Replacement of L-amino acid peptides with D-amino acid peptides mitigates anti-PEG antibody generation against polymer-peptide conjugates in mice. J. Control. Release 331 , 142–153 (2021). 33444669 10.1016/j.jconrel.2021.01.015 PMC7946756

187. Werner HM Cabalteja CC Horne WS Peptide Backbone Composition and Protease Susceptibility: Impact of Modification Type, Position, and Tandem Substitution ChemBioChem 2016 17 712 718 10.1002/cbic.201500312 26205791 PMC4721950 Werner, H. M., Cabalteja, C. C. & Horne, W. S. Peptide Backbone Composition and Protease Susceptibility: Impact of Modification Type, Position, and Tandem Substitution. ChemBioChem 17 , 712–718 (2016). 26205791 10.1002/cbic.201500312 PMC4721950

188. Li X Backbone N-methylation of peptides: Advances in synthesis and applications in pharmaceutical drug development Bioorg. Chem. 2023 141 106892 10.1016/j.bioorg.2023.106892 37776681 Li, X. et al. Backbone N-methylation of peptides: Advances in synthesis and applications in pharmaceutical drug development. Bioorg. Chem. 141 , 106892 (2023). 37776681 10.1016/j.bioorg.2023.106892

189. Asano A Yamada T Doi M Incorporation of β-amino acids into ascidiacyclamides: Effects on conformation, cytotoxicity and interaction with copper (II) ion J. Pept. Sci. 2020 26 e3225 10.1002/psc.3225 31713938 Asano, A., Yamada, T. & Doi, M. Incorporation of β-amino acids into ascidiacyclamides: Effects on conformation, cytotoxicity and interaction with copper (II) ion. J. Pept. Sci. 26 , e3225 (2020). 31713938 10.1002/psc.3225

190. Cheloha RW Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist ACS Chem. Biol. 2016 11 2752 2762 10.1021/acschembio.6b00404 27533344 PMC5107307 Cheloha, R. W. et al. Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem. Biol. 11 , 2752–2762 (2016). 27533344 10.1021/acschembio.6b00404 PMC5107307

191. Tyler TJ Durek T Craik DJ Native and Engineered Cyclic Disulfide-Rich Peptides as Drug Leads Molecules 2023 28 3189 10.3390/molecules28073189 37049950 PMC10096437 Tyler, T. J., Durek, T. & Craik, D. J. Native and Engineered Cyclic Disulfide-Rich Peptides as Drug Leads. Molecules 28 , 3189 (2023). 37049950 10.3390/molecules28073189 PMC10096437

192. Ayikpoe RS van der Donk WA Peptide backbone modifications in lanthipeptides Methods Enzymol. 2021 656 573 621 10.1016/bs.mie.2021.04.012 34325799 Ayikpoe, R. S. & van der Donk, W. A. Peptide backbone modifications in lanthipeptides. Methods Enzymol. 656 , 573–621 (2021). 34325799 10.1016/bs.mie.2021.04.012

193. Fan Cheng K VanPatten S He M Al-Abed Y Azapeptides -A History of Synthetic Milestones and Key Examples Curr. Med. Chem. 2022 29 6336 6358 10.2174/0929867329666220510214402 35538801 Fan Cheng, K., VanPatten, S., He, M. & Al-Abed, Y. Azapeptides -A History of Synthetic Milestones and Key Examples. Curr. Med. Chem. 29 , 6336–6358 (2022). 35538801 10.2174/0929867329666220510214402

194. Preston GW Different directions for retro-inverso peptides J. Pept. Sci. 2022 28 e3384 10.1002/psc.3384 34889485 Preston, G. W. Different directions for retro-inverso peptides. J. Pept. Sci. 28 , e3384 (2022). 34889485 10.1002/psc.3384

195. Zhu J Recent advances in anticancer peptoids Bioorg. Chem. 2023 139 106686 10.1016/j.bioorg.2023.106686 37399616 Zhu, J. et al. Recent advances in anticancer peptoids. Bioorg. Chem. 139 , 106686 (2023). 37399616 10.1016/j.bioorg.2023.106686

196. Vanhoutte R Azapeptide activity-based probes for the SARS-CoV-2 main protease enable visualization of inhibition in infected cells Chem. Sci. 2023 14 1666 1672 10.1039/D2SC04147B 36819852 PMC9931053 Vanhoutte, R. et al. Azapeptide activity-based probes for the SARS-CoV-2 main protease enable visualization of inhibition in infected cells. Chem. Sci. 14 , 1666–1672 (2023). 36819852 10.1039/d2sc04147b PMC9931053

197. Lombardi A Retro-inverso D-peptides as a novel targeted immunotherapy for Type 1 diabetes J. Autoimmun. 2020 115 102543 10.1016/j.jaut.2020.102543 32951964 PMC7683378 Lombardi, A. et al. Retro-inverso D-peptides as a novel targeted immunotherapy for Type 1 diabetes. J. Autoimmun. 115 , 102543 (2020). 32951964 10.1016/j.jaut.2020.102543 PMC7683378

198. Sun J Protective effect of urotensin II receptor antagonist urantide and exercise training on doxorubicin-induced cardiotoxicity Sci. Rep. 2023 13 1279 10.1038/s41598-023-28437-y 36690700 PMC9870887 Sun, J. et al. Protective effect of urotensin II receptor antagonist urantide and exercise training on doxorubicin-induced cardiotoxicity. Sci. Rep. 13 , 1279 (2023). 36690700 10.1038/s41598-023-28437-y PMC9870887

199. Ma S A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells Pulm. Pharmacol. Ther. 2023 78 102185 10.1016/j.pupt.2022.102185 36563740 Ma, S. et al. A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells. Pulm. Pharmacol. Ther. 78 , 102185 (2023). 36563740 10.1016/j.pupt.2022.102185

200. Giorgio A Peptoids: Smart and Emerging Candidates for the Diagnosis of Cancer, Neurological and Autoimmune Disorders Int. J. Mol. Sci. 2023 24 16333 10.3390/ijms242216333 38003529 PMC10671428 Giorgio, A. et al. Peptoids: Smart and Emerging Candidates for the Diagnosis of Cancer, Neurological and Autoimmune Disorders. Int. J. Mol. Sci. 24 , 16333 (2023). 38003529 10.3390/ijms242216333 PMC10671428

201. Masri E Ahsanullah Accorsi M Rademann J Side-Chain Modification of Peptides Using a Phosphoranylidene Amino Acid Org. Lett. 2020 22 2976 2980 10.1021/acs.orglett.0c00713 32223201 Masri, E., Ahsanullah, Accorsi, M. & Rademann, J. Side-Chain Modification of Peptides Using a Phosphoranylidene Amino Acid. Org. Lett. 22 , 2976–2980 (2020). 32223201 10.1021/acs.orglett.0c00713

202. Fotso S Alveolarides: Antifungal Peptides from Microascus alveolaris Active against Phytopathogenic Fungi J. Nat. Prod. 2018 81 10 15 10.1021/acs.jnatprod.7b00337 29283257 Fotso, S. et al. Alveolarides: Antifungal Peptides from Microascus alveolaris Active against Phytopathogenic Fungi. J. Nat. Prod. 81 , 10–15 (2018). 29283257 10.1021/acs.jnatprod.7b00337

203. Sakamoto K Use of homoarginine to obtain attenuated cationic membrane lytic peptides Bioorg. Med. Chem. Lett. 2021 40 127925 10.1016/j.bmcl.2021.127925 33705909 Sakamoto, K. et al. Use of homoarginine to obtain attenuated cationic membrane lytic peptides. Bioorg. Med. Chem. Lett. 40 , 127925 (2021). 33705909 10.1016/j.bmcl.2021.127925

204. Michie MS Side-chain modification of collagen-targeting peptide prevents dye aggregation for improved molecular imaging of arthritic joints J. Photochem. Photobiol. A: Chem. 2022 424 113624 10.1016/j.jphotochem.2021.113624 36406204 PMC9673490 Michie, M. S. et al. Side-chain modification of collagen-targeting peptide prevents dye aggregation for improved molecular imaging of arthritic joints. J. Photochem. Photobiol. A: Chem. 424 , 113624 (2022). 36406204 10.1016/j.jphotochem.2021.113624 PMC9673490

205. Thompson GR III Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial Lancet 2023 401 49 59 10.1016/S0140-6736(22)02324-8 36442484 Thompson, G. R. III et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet 401 , 49–59 (2023). 36442484 10.1016/S0140-6736(22)02324-8

206. Crees ZD Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial Nat. Med. 2023 29 869 879 10.1038/s41591-023-02273-z 37069359 PMC10115633 Crees, Z. D. et al. Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial. Nat. Med. 29 , 869–879 (2023). 37069359 10.1038/s41591-023-02273-z PMC10115633

207. Howard JF Jr. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study Lancet Neurol. 2023 22 395 406 10.1016/S1474-4422(23)00080-7 37059508 Howard, J. F. Jr. et al. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 22 , 395–406 (2023). 37059508 10.1016/S1474-4422(23)00080-7

208. Mourão CBF Head-to-Tail Cyclization after Interaction with Trypsin: A Scorpion Venom Peptide that Resembles Plant Cyclotides J. Med. Chem. 2020 63 9500 9511 10.1021/acs.jmedchem.0c00686 32787139 Mourão, C. B. F. et al. Head-to-Tail Cyclization after Interaction with Trypsin: A Scorpion Venom Peptide that Resembles Plant Cyclotides. J. Med. Chem. 63 , 9500–9511 (2020). 32787139 10.1021/acs.jmedchem.0c00686

209. Yang P-Y Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models J. Med. Chem. 2018 61 3218 3223 10.1021/acs.jmedchem.7b00768 29528634 Yang, P.-Y. et al. Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models. J. Med. Chem. 61 , 3218–3223 (2018). 29528634 10.1021/acs.jmedchem.7b00768

210. Ricardo MG Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein–Protein Interactions Angew. Chem. Int. Ed. 2020 59 5235 5241 10.1002/anie.201916257 31944488 Ricardo, M. G. et al. Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein–Protein Interactions. Angew. Chem. Int. Ed. 59 , 5235–5241 (2020). 10.1002/anie.201916257 31944488

211. Li CY Binding Loop Substitutions in the Cyclic Peptide SFTI-1 Generate Potent and Selective Chymase Inhibitors J. Med. Chem. 2020 63 816 826 10.1021/acs.jmedchem.9b01811 31855419 Li, C. Y. et al. Binding Loop Substitutions in the Cyclic Peptide SFTI-1 Generate Potent and Selective Chymase Inhibitors. J. Med. Chem. 63 , 816–826 (2020). 31855419 10.1021/acs.jmedchem.9b01811

212. Damjanovic J Miao J Huang H Lin Y-S Elucidating solution structures of cyclic peptides using molecular dynamics simulations Chem. Rev. 2021 121 2292 2324 10.1021/acs.chemrev.0c01087 33426882 PMC8340081 Damjanovic, J., Miao, J., Huang, H. & Lin, Y.-S. Elucidating solution structures of cyclic peptides using molecular dynamics simulations. Chem. Rev. 121 , 2292–2324 (2021). 33426882 10.1021/acs.chemrev.0c01087 PMC8340081

213. Váradi G Rational Design of Antifungal Peptides Based on the γ-Core Motif of a Neosartorya (Aspergillus) fischeri Antifungal Protein to Improve Structural Integrity, Efficacy, and Spectrum ACS Omega 2024 9 7206 7214 10.1021/acsomega.3c09377 38371770 PMC10870298 Váradi, G. et al. Rational Design of Antifungal Peptides Based on the γ-Core Motif of a Neosartorya (Aspergillus) fischeri Antifungal Protein to Improve Structural Integrity, Efficacy, and Spectrum. ACS Omega 9 , 7206–7214 (2024). 38371770 10.1021/acsomega.3c09377 PMC10870298

214. Linker SM Lessons for oral bioavailability: how conformationally flexible cyclic peptides enter and cross lipid membranes J. Med. Chem. 2023 66 2773 2788 10.1021/acs.jmedchem.2c01837 36762908 PMC9969412 Linker, S. M. et al. Lessons for oral bioavailability: how conformationally flexible cyclic peptides enter and cross lipid membranes. J. Med. Chem. 66 , 2773–2788 (2023). 36762908 10.1021/acs.jmedchem.2c01837 PMC9969412

215. Patocka J Nepovimova E Kuca K Wu W Cyclosporine A: Chemistry and Toxicity - A Review Curr. Med. Chem. 2021 28 3925 3934 10.2174/0929867327666201006153202 33023428 Patocka, J., Nepovimova, E., Kuca, K. & Wu, W. Cyclosporine A: Chemistry and Toxicity - A Review. Curr. Med. Chem. 28 , 3925–3934 (2021). 33023428 10.2174/0929867327666201006153202

216. Heo Y-A Voclosporin: First Approval Drugs 2021 81 605 610 10.1007/s40265-021-01488-z 33788181 PMC8010786 Heo, Y.-A. Voclosporin: First Approval. Drugs 81 , 605–610 (2021). 33788181 10.1007/s40265-021-01488-z PMC8010786

217. Goad N Levesque M Role of desmopressin in the critical care setting AACN Adv. Crit. Care. 2020 31 5 11 10.4037/aacnacc2020815 32168509 Goad, N. & Levesque, M. Role of desmopressin in the critical care setting. AACN Adv. Crit. Care. 31 , 5–11 (2020). 32168509 10.4037/aacnacc2020815

218. Burnett JR Hooper AJ MK-0616: An oral PCSK9 inhibitor for hypercholesterolemia treatment Expert Opin. Investig. Drugs 2023 32 873 878 10.1080/13543784.2023.2267972 37815341 Burnett, J. R. & Hooper, A. J. MK-0616: An oral PCSK9 inhibitor for hypercholesterolemia treatment. Expert Opin. Investig. Drugs 32 , 873–878 (2023). 37815341 10.1080/13543784.2023.2267972

219. Li X Chen S Zhang W-D Hu H-G Stapled Helical Peptides Bearing Different Anchoring Residues Chem. Rev. 2020 120 10079 10144 10.1021/acs.chemrev.0c00532 32794722 Li, X., Chen, S., Zhang, W.-D. & Hu, H.-G. Stapled Helical Peptides Bearing Different Anchoring Residues. Chem. Rev. 120 , 10079–10144 (2020). 32794722 10.1021/acs.chemrev.0c00532

220. Tzotzos S Stapled peptides as potential inhibitors of SARS-CoV-2 binding to the hACE2 receptor J. Pept. Sci. 2022 28 e3409 10.1002/psc.3409 35165970 PMC9111031 Tzotzos, S. Stapled peptides as potential inhibitors of SARS-CoV-2 binding to the hACE2 receptor. J. Pept. Sci. 28 , e3409 (2022). 35165970 10.1002/psc.3409 PMC9111031

221. Kijewska M Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity Chem. Commun. (Camb.). 2024 60 3023 3026 10.1039/D3CC06345C 38356394 Kijewska, M. et al. Stapling of leu-enkephalin analogs with bifunctional reagents for prolonged analgesic activity. Chem. Commun. (Camb.). 60 , 3023–3026 (2024). 38356394 10.1039/d3cc06345c

222. Guo P Peptide Stapling by Crosslinking Two Amines with α-Ketoaldehydes through Diverse Modified Glyoxal-Lysine Dimer Linkers Angew. Chem. Int Ed. Engl. 2024 63 e202318893 10.1002/anie.202318893 38376389 Guo, P. et al. Peptide Stapling by Crosslinking Two Amines with α-Ketoaldehydes through Diverse Modified Glyoxal-Lysine Dimer Linkers. Angew. Chem. Int Ed. Engl. 63 , e202318893 (2024). 38376389 10.1002/anie.202318893

223. Ricardo MG Vasco AV Rivera DG Wessjohann LA Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns Org. Lett. 2019 21 7307 7310 10.1021/acs.orglett.9b02592 31482710 Ricardo, M. G., Vasco, A. V., Rivera, D. G. & Wessjohann, L. A. Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns. Org. Lett. 21 , 7307–7310 (2019). 31482710 10.1021/acs.orglett.9b02592

224. Khoo KK Lactam-Stabilized Helical Analogues of the Analgesic μ-Conotoxin KIIIA J. Med. Chem. 2011 54 7558 7566 10.1021/jm200839a 21962108 PMC3228837 Khoo, K. K. et al. Lactam-Stabilized Helical Analogues of the Analgesic μ-Conotoxin KIIIA. J. Med. Chem. 54 , 7558–7566 (2011). 21962108 10.1021/jm200839a PMC3228837

225. Irie H Tyrosinase-Related Protein2 Peptide with Replacement of N-Terminus Residue by Cysteine Binds to H-2Kb and Induces Antigen-Specific Cytotoxic T Lymphocytes after Conjugation with CpG-DNA Bioconjugate Chem. 2023 34 433 442 10.1021/acs.bioconjchem.2c00592 36708315 Irie, H. et al. Tyrosinase-Related Protein2 Peptide with Replacement of N-Terminus Residue by Cysteine Binds to H-2Kb and Induces Antigen-Specific Cytotoxic T Lymphocytes after Conjugation with CpG-DNA. Bioconjugate Chem. 34 , 433–442 (2023). 10.1021/acs.bioconjchem.2c00592 36708315

226. Muppidi A Design of antiviral stapled peptides containing a biphenyl cross-linker Bioorg. Med. Chem. Lett. 2014 24 1748 1751 10.1016/j.bmcl.2014.02.038 24613163 PMC4005879 Muppidi, A. et al. Design of antiviral stapled peptides containing a biphenyl cross-linker. Bioorg. Med. Chem. Lett. 24 , 1748–1751 (2014). 24613163 10.1016/j.bmcl.2014.02.038 PMC4005879

227. Nolan MD Schüttel M Scanlan EM Nielsen AL Nanomole-scale photochemical thiol-ene chemistry for high-throughput late-stage diversification of peptide macrocycles Pept. Sci. 2024 116 e24310 10.1002/pep2.24310 Nolan, M. D., Schüttel, M., Scanlan, E. M. & Nielsen, A. L. Nanomole-scale photochemical thiol-ene chemistry for high-throughput late-stage diversification of peptide macrocycles. Pept. Sci. 116 , e24310 (2024).

228. Malhis M Funke SA Mirror-Image Phage Display for the Selection of D-Amino Acid Peptide Ligands as Potential Therapeutics Curr. Protoc. 2024 4 e957 10.1002/cpz1.957 38372457 PMC13014060 Malhis, M. & Funke, S. A. Mirror-Image Phage Display for the Selection of D-Amino Acid Peptide Ligands as Potential Therapeutics. Curr. Protoc. 4 , e957 (2024). 38372457 10.1002/cpz1.957 PMC13014060

229. Nazzaro A Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates Angew. Chem. Int. Ed. 2023 62 e202303943 10.1002/anie.202303943 PMC10592574 37170337 Nazzaro, A. et al. Macrocyclic β-Sheets Stabilized by Hydrogen Bond Surrogates. Angew. Chem. Int. Ed. 62 , e202303943 (2023). 10.1002/anie.202303943 PMC10592574 37170337

230. Yu L Experimental Insights into Conformational Ensembles of Assembled β-Sheet Peptides ACS Cent. Sci. 2023 9 1480 1487 10.1021/acscentsci.3c00230 37521785 PMC10375872 Yu, L. et al. Experimental Insights into Conformational Ensembles of Assembled β-Sheet Peptides. ACS Cent. Sci. 9 , 1480–1487 (2023). 37521785 10.1021/acscentsci.3c00230 PMC10375872

231. Myšková A Sýkora D Kuneš J Maletínská L Lipidization as a tool toward peptide therapeutics Drug Deliv. 2023 30 2284685 10.1080/10717544.2023.2284685 38010881 PMC10987053 Myšková, A., Sýkora, D., Kuneš, J. & Maletínská, L. Lipidization as a tool toward peptide therapeutics. Drug Deliv. 30 , 2284685 (2023). 38010881 10.1080/10717544.2023.2284685 PMC10987053

232. Bartlett S Skwarczynski M Toth I Lipids as Activators of Innate Immunity in Peptide Vaccine Delivery Curr. Med. Chem. 2020 27 2887 2901 10.2174/0929867325666181026100849 30362416 Bartlett, S., Skwarczynski, M. & Toth, I. Lipids as Activators of Innate Immunity in Peptide Vaccine Delivery. Curr. Med. Chem. 27 , 2887–2901 (2020). 30362416 10.2174/0929867325666181026100849

233. Kurtzhals P Østergaard S Nishimura E Kjeldsen T Derivatization with fatty acids in peptide and protein drug discovery Nat. Rev. Drug Discov. 2023 22 59 80 10.1038/s41573-022-00529-w 36002588 Kurtzhals, P., Østergaard, S., Nishimura, E. & Kjeldsen, T. Derivatization with fatty acids in peptide and protein drug discovery. Nat. Rev. Drug Discov. 22 , 59–80 (2023). 36002588 10.1038/s41573-022-00529-w

234. Irby D Du C Li F Lipid–Drug Conjugate for Enhancing Drug Delivery Mol. Pharm. 2017 14 1325 1338 10.1021/acs.molpharmaceut.6b01027 28080053 PMC5477224 Irby, D., Du, C. & Li, F. Lipid–Drug Conjugate for Enhancing Drug Delivery. Mol. Pharm. 14 , 1325–1338 (2017). 28080053 10.1021/acs.molpharmaceut.6b01027 PMC5477224

235. Bhat M Opportunities and challenges of fatty acid conjugated therapeutics Chem. Phys. Lipids 2021 236 105053 10.1016/j.chemphyslip.2021.105053 33484709 Bhat, M. et al. Opportunities and challenges of fatty acid conjugated therapeutics. Chem. Phys. Lipids 236 , 105053 (2021). 33484709 10.1016/j.chemphyslip.2021.105053

236. Van Lysebetten D Lipid-Polyglutamate Nanoparticle Vaccine Platform ACS Appl. Mater. Interfaces 2021 13 6011 6022 10.1021/acsami.0c20607 33507728 PMC7116839 Van Lysebetten, D. et al. Lipid-Polyglutamate Nanoparticle Vaccine Platform. ACS Appl. Mater. Interfaces 13 , 6011–6022 (2021). 33507728 10.1021/acsami.0c20607 PMC7116839

237. Manteghi R Pallagi E Olajos G Csóka I Pegylation and formulation strategy of Anti-Microbial Peptide (AMP) according to the quality by design approach Eur. J. Pharm. Sci. 2020 144 105197 10.1016/j.ejps.2019.105197 31862311 Manteghi, R., Pallagi, E., Olajos, G. & Csóka, I. Pegylation and formulation strategy of Anti-Microbial Peptide (AMP) according to the quality by design approach. Eur. J. Pharm. Sci. 144 , 105197 (2020). 31862311 10.1016/j.ejps.2019.105197

238. Schlesinger N Yasothan U Kirkpatrick P Pegloticase Nat. Rev. Drug Discov. 2011 10 17 18 10.1038/nrd3349 21193861 Schlesinger, N., Yasothan, U. & Kirkpatrick, P. Pegloticase. Nat. Rev. Drug Discov. 10 , 17–18 (2011). 21193861 10.1038/nrd3349

239. Lucana MC Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics Pharmaceutics 2021 13 2065 10.3390/pharmaceutics13122065 34959346 PMC8708026 Lucana, M. C. et al. Protease-Resistant Peptides for Targeting and Intracellular Delivery of Therapeutics. Pharmaceutics 13 , 2065 (2021). 34959346 10.3390/pharmaceutics13122065 PMC8708026

240. Soleymani-Goloujeh M Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides Artif. Cell. Nanomed. Biotechnol. 2018 46 91 103 10.1080/21691401.2017.1414823 29258339 Soleymani-Goloujeh, M. et al. Effects of N-terminal and C-terminal modification on cytotoxicity and cellular uptake of amphiphilic cell penetrating peptides. Artif. Cell. Nanomed. Biotechnol. 46 , 91–103 (2018). 10.1080/21691401.2017.1414823 29258339

241. Tao H-y Wang R-q Sheng W-j Zhen Y-s The development of human serum albumin-based drugs and relevant fusion proteins for cancer therapy Int. J. Biol. Macromol. 2021 187 24 34 10.1016/j.ijbiomac.2021.07.080 34284054 Tao, H.-y, Wang, R.-q, Sheng, W.-j & Zhen, Y.-s The development of human serum albumin-based drugs and relevant fusion proteins for cancer therapy. Int. J. Biol. Macromol. 187 , 24–34 (2021). 34284054 10.1016/j.ijbiomac.2021.07.080

242. Furukawa N Popel AS Peptides that immunoactivate the tumor microenvironment Biochim. Biophys. Acta 2021 1875 188486 10.1016/j.bbcan.2020.188486 PMC8369429 33276025 Furukawa, N. & Popel, A. S. Peptides that immunoactivate the tumor microenvironment. Biochim. Biophys. Acta 1875 , 188486 (2021). 10.1016/j.bbcan.2020.188486 PMC8369429 33276025

243. Bak M Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide Pharmaceutics 2020 12 364 10.3390/pharmaceutics12040364 32316169 PMC7238188 Bak, M. et al. Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide. Pharmaceutics 12 , 364 (2020). 32316169 10.3390/pharmaceutics12040364 PMC7238188

244. Singh A Srivastava V Multi-functional Chimeric Peptides: The More the Merrier Protein Pept. Lett. 2018 25 1090 1100 10.2174/0929866525666181120090857 30457042 Singh, A. & Srivastava, V. Multi-functional Chimeric Peptides: The More the Merrier. Protein Pept. Lett. 25 , 1090–1100 (2018). 30457042 10.2174/0929866525666181120090857

245. Gomari MM Peptidomimetics in cancer targeting Mol. Med. 2022 28 146 10.1186/s10020-022-00577-3 36476230 PMC9730693 Gomari, M. M. et al. Peptidomimetics in cancer targeting. Mol. Med. 28 , 146 (2022). 36476230 10.1186/s10020-022-00577-3 PMC9730693

246. Ding D Medicinal chemistry insights into antiviral peptidomimetics Drug Discov. Today 2023 28 103468 10.1016/j.drudis.2022.103468 36528280 Ding, D. et al. Medicinal chemistry insights into antiviral peptidomimetics. Drug Discov. Today 28 , 103468 (2023). 36528280 10.1016/j.drudis.2022.103468

247. Zizzari AT New perspectives in oral peptide delivery Drug Discov. Today 2021 26 1097 1105 10.1016/j.drudis.2021.01.020 33497830 Zizzari, A. T. et al. New perspectives in oral peptide delivery. Drug Discov. Today 26 , 1097–1105 (2021). 33497830 10.1016/j.drudis.2021.01.020

248. Fernández-Carvajal A González-Muñiz R Fernández-Ballester G Ferrer-Montiel A Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels Expert Opin. Investig. Drugs 2020 29 1209 1222 10.1080/13543784.2020.1825680 32941080 Fernández-Carvajal, A., González-Muñiz, R., Fernández-Ballester, G. & Ferrer-Montiel, A. Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels. Expert Opin. Investig. Drugs 29 , 1209–1222 (2020). 32941080 10.1080/13543784.2020.1825680

249. Ferrazzano L Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges Green. Chem. 2022 24 975 1020 10.1039/D1GC04387K Ferrazzano, L. et al. Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges. Green. Chem. 24 , 975–1020 (2022).

250. Khalily MP Soydan M Peptide-based diagnostic and therapeutic agents: Where we are and where we are heading? Chem. Biol. Drug Des. 2023 101 772 793 10.1111/cbdd.14180 36366980 Khalily, M. P. & Soydan, M. Peptide-based diagnostic and therapeutic agents: Where we are and where we are heading? Chem. Biol. Drug Des. 101 , 772–793 (2023). 36366980 10.1111/cbdd.14180

251. Allison DB Obesity as a disease: a white paper on evidence and arguments commissioned by the Council of the Obesity Society Obes. (Silver Spring) 2008 16 1161 1177 10.1038/oby.2008.231 18464753 Allison, D. B. et al. Obesity as a disease: a white paper on evidence and arguments commissioned by the Council of the Obesity Society. Obes. (Silver Spring) 16 , 1161–1177 (2008). 10.1038/oby.2008.231 18464753

252. Zhao X GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects Front Endocrinol. (Lausanne) 2021 12 721135 10.3389/fendo.2021.721135 34497589 PMC8419463 Zhao, X. et al. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol. (Lausanne) 12 , 721135 (2021). 34497589 10.3389/fendo.2021.721135 PMC8419463

253. Ryan DH Yockey SR Weight Loss and Improvement in Comorbidity: Differences at 5%, 10%, 15%, and Over Curr. Obes. Rep. 2017 6 187 194 10.1007/s13679-017-0262-y 28455679 PMC5497590 Ryan, D. H. & Yockey, S. R. Weight Loss and Improvement in Comorbidity: Differences at 5%, 10%, 15%, and Over. Curr. Obes. Rep. 6 , 187–194 (2017). 28455679 10.1007/s13679-017-0262-y PMC5497590

254. Kolotkin RL Andersen JR A systematic review of reviews: exploring the relationship between obesity, weight loss and health-related quality of life Clin. Obes. 2017 7 273 289 10.1111/cob.12203 28695722 PMC5600094 Kolotkin, R. L. & Andersen, J. R. A systematic review of reviews: exploring the relationship between obesity, weight loss and health-related quality of life. Clin. Obes. 7 , 273–289 (2017). 28695722 10.1111/cob.12203 PMC5600094

255. Wing RR Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes Diabetes Care 2011 34 1481 1486 10.2337/dc10-2415 21593294 PMC3120182 Wing, R. R. et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 34 , 1481–1486 (2011). 21593294 10.2337/dc10-2415 PMC3120182

256. Bliss M The discovery of insulin: the inside story Publ. Am. Inst. Hist. Pharm. 1997 16 93 99 11619903 Bliss, M. The discovery of insulin: the inside story. Publ. Am. Inst. Hist. Pharm. 16 , 93–99 (1997). 11619903

257. Dingermann T Recombinant therapeutic proteins: production platforms and challenges Biotechnol. J. 2008 3 90 97 10.1002/biot.200700214 18041103 Dingermann, T. Recombinant therapeutic proteins: production platforms and challenges. Biotechnol. J. 3 , 90–97 (2008). 18041103 10.1002/biot.200700214

258. Goeddel DV Expression in Escherichia coli of chemically synthesized genes for human insulin Proc. Natl Acad. Sci. USA 1979 76 106 110 10.1073/pnas.76.1.106 85300 PMC382885 Goeddel, D. V. et al. Expression in Escherichia coli of chemically synthesized genes for human insulin. Proc. Natl Acad. Sci. USA 76 , 106–110 (1979).Visualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figure 85300 10.1073/pnas.76.1.106 PMC382885

259. Akbarian M Ghasemi Y Uversky VN Yousefi R Chemical modifications of insulin: Finding a compromise between stability and pharmaceutical performance Int J. Pharm. 2018 547 450 468 10.1016/j.ijpharm.2018.06.023 29890260 Akbarian, M., Ghasemi, Y., Uversky, V. N. & Yousefi, R. Chemical modifications of insulin: Finding a compromise between stability and pharmaceutical performance. Int J. Pharm. 547 , 450–468 (2018).Visualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figureVisualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figure 29890260 10.1016/j.ijpharm.2018.06.023

260. Monnier L Colette C Owens D Acylated-based long-acting insulin analogues: is “misfolding” the problem? Commentary letter on Hamasaki H and Yanai H. The switching from insulin glargine to insulin degludec reduced HbA1c, daily insulin doses and anti-insulin antibody in anti-insulin antibody-positive subjects with type 1 diabetes Diabetes Metab. 2014 40 483 484 10.1016/j.diabet.2014.10.001 25459321 Monnier, L., Colette, C. & Owens, D. Acylated-based long-acting insulin analogues: is “misfolding” the problem? Commentary letter on Hamasaki H and Yanai H. The switching from insulin glargine to insulin degludec reduced HbA1c, daily insulin doses and anti-insulin antibody in anti-insulin antibody-positive subjects with type 1 diabetes. Diabetes Metab. 40 , 483–484 (2014).Visualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figureVisualization of important events in the development of peptide drugs. In this figure, important peptide drugs are classified according to the disease to which they correspond. In addition, the progress of optimization strategy of peptide drugs and Cell-penetrating peptides are also listed in this figure 25459321 10.1016/j.diabet.2014.10.001

261. Akbarian M Yousefi R Farjadian F Uversky VN Insulin fibrillation: toward strategies for attenuating the process Chem. Commun. (Camb.). 2020 56 11354 11373 10.1039/D0CC05171C 32990302 Akbarian, M., Yousefi, R., Farjadian, F. & Uversky, V. N. Insulin fibrillation: toward strategies for attenuating the process. Chem. Commun. (Camb.). 56 , 11354–11373 (2020). 32990302 10.1039/d0cc05171c

262. Kimball CP Murlin JR Aqueous Extracts of Pancreas:III. Some Precipitation Reactions of Insulin J. Biol. Chem. 1923 58 337 346 10.1016/S0021-9258(18)85474-6 Kimball, C. P. & Murlin, J. R. Aqueous Extracts of Pancreas:III. Some Precipitation Reactions of Insulin. J. Biol. Chem. 58 , 337–346 (1923).

263. Marzook A Tomas A Jones B The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells Front Endocrinol. (Lausanne) 2021 12 678055 10.3389/fendo.2021.678055 34040588 PMC8143046 Marzook, A., Tomas, A. & Jones, B. The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells. Front Endocrinol. (Lausanne) 12 , 678055 (2021). 34040588 10.3389/fendo.2021.678055 PMC8143046

264. Smits MM Van Raalte DH Safety of Semaglutide Front Endocrinol. (Lausanne) 2021 12 645563 10.3389/fendo.2021.645563 34305810 PMC8294388 Smits, M. M. & Van Raalte, D. H. Safety of Semaglutide. Front Endocrinol. (Lausanne) 12 , 645563 (2021). 34305810 10.3389/fendo.2021.645563 PMC8294388

265. Ha JH Kim JE Kim YS Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins Front. Immunol. 2016 7 394 10.3389/fimmu.2016.00394 27766096 PMC5052280 Ha, J. H., Kim, J. E. & Kim, Y. S. Immunoglobulin Fc Heterodimer Platform Technology: From Design to Applications in Therapeutic Antibodies and Proteins. Front. Immunol. 7 , 394 (2016). 27766096 10.3389/fimmu.2016.00394 PMC5052280

266. Baggio LL Drucker DJ Biology of incretins: GLP-1 and GIP Gastroenterology 2007 132 2131 2157 10.1053/j.gastro.2007.03.054 17498508 Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132 , 2131–2157 (2007). 17498508 10.1053/j.gastro.2007.03.054

267. Frias JP Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial Lancet 2018 392 2180 2193 10.1016/S0140-6736(18)32260-8 30293770 Frias, J. P. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392 , 2180–2193 (2018). 30293770 10.1016/S0140-6736(18)32260-8

268. Frías JP Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes N. Engl. J. Med 2021 385 503 515 10.1056/NEJMoa2107519 34170647 Frías, J. P. et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N. Engl. J. Med 385 , 503–515 (2021). 34170647 10.1056/NEJMoa2107519

269. le Roux CW Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program Obes. (Silver Spring) 2023 31 96 110 10.1002/oby.23612 PMC10107501 36478180 le Roux, C. W. et al. Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program. Obes. (Silver Spring) 31 , 96–110 (2023). 10.1002/oby.23612 PMC10107501 36478180

270. Wang L Designing a dual GLP-1R/GIPR Agonist from Tirzepatide: comparing residues between Tirzepatide, GLP-1, and GIP Drug Des. Devel. Ther. 2022 16 1547 1559 10.2147/DDDT.S358989 35651477 PMC9149770 Wang, L. Designing a dual GLP-1R/GIPR Agonist from Tirzepatide: comparing residues between Tirzepatide, GLP-1, and GIP. Drug Des. Devel. Ther. 16 , 1547–1559 (2022). 35651477 10.2147/DDDT.S358989 PMC9149770

271. Coskun T LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept Cell Metab. 2022 34 1234 1247.e1239 10.1016/j.cmet.2022.07.013 35985340 Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 34 , 1234–1247.e1239 (2022). 35985340 10.1016/j.cmet.2022.07.013

272. Doggrell SA Retatrutide showing promise in obesity (and type 2 diabetes) Expert Opin. Investig. Drugs 2023 32 997 1001 10.1080/13543784.2023.2283020 37947489 Doggrell, S. A. Retatrutide showing promise in obesity (and type 2 diabetes). Expert Opin. Investig. Drugs 32 , 997–1001 (2023). 37947489 10.1080/13543784.2023.2283020

273. Chen J The role of C-peptide in diabetes and its complications: an updated review Front Endocrinol. (Lausanne) 2023 14 1256093 10.3389/fendo.2023.1256093 37745697 PMC10512826 Chen, J. et al. The role of C-peptide in diabetes and its complications: an updated review. Front Endocrinol. (Lausanne) 14 , 1256093 (2023). 37745697 10.3389/fendo.2023.1256093 PMC10512826

274. Wagner S Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression Mol. Metab. 2023 68 101665 10.1016/j.molmet.2022.101665 36592795 PMC9841057 Wagner, S. et al. Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression. Mol. Metab. 68 , 101665 (2023). 36592795 10.1016/j.molmet.2022.101665 PMC9841057

275. Zheng J GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease Mol. Metab. 2021 47 101180 10.1016/j.molmet.2021.101180 33556642 PMC7905479 Zheng, J. et al. GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease. Mol. Metab. 47 , 101180 (2021). 33556642 10.1016/j.molmet.2021.101180 PMC7905479

276. Sung H Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J. Clin. 2021 71 209 249 10.3322/caac.21660 33538338 Sung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 71 , 209–249 (2021). 33538338 10.3322/caac.21660

277. Cai Z Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis of the literature from the past 20 years Surg. Oncol. 2018 27 563 574 10.1016/j.suronc.2018.07.011 30217320 Cai, Z. et al. Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis of the literature from the past 20 years. Surg. Oncol. 27 , 563–574 (2018). 30217320 10.1016/j.suronc.2018.07.011

278. Yu W-D Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy Cancer Lett. 2019 452 66 70 10.1016/j.canlet.2019.02.048 30902563 Yu, W.-D. et al. Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy. Cancer Lett. 452 , 66–70 (2019). 30902563 10.1016/j.canlet.2019.02.048

279. Aljabery F The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer Urol. Oncol. 2018 36 530.e537 530.e518 10.1016/j.urolonc.2018.05.025 30539751 Aljabery, F. et al. The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer. Urol. Oncol. 36 , 530.e537–530.e518 (2018). 10.1016/j.urolonc.2018.05.025 30539751

280. Luo Q Zhang L Luo C Jiang M Emerging strategies in cancer therapy combining chemotherapy with immunotherapy Cancer Lett. 2019 454 191 203 10.1016/j.canlet.2019.04.017 30998963 Luo, Q., Zhang, L., Luo, C. & Jiang, M. Emerging strategies in cancer therapy combining chemotherapy with immunotherapy. Cancer Lett. 454 , 191–203 (2019). 30998963 10.1016/j.canlet.2019.04.017

281. Wang X Cancer immunotherapy for metastasis: past, present and future Brief. Funct. Genomics 2019 18 140 146 10.1093/bfgp/ely022 29992233 Wang, X. et al. Cancer immunotherapy for metastasis: past, present and future. Brief. Funct. Genomics 18 , 140–146 (2019). 29992233 10.1093/bfgp/ely022

282. Yang K Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia Pathol. - Res. Pract. 2019 215 265 271 10.1016/j.prp.2018.10.021 30466764 Yang, K. et al. Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia. Pathol. - Res. Pract. 215 , 265–271 (2019). 30466764 10.1016/j.prp.2018.10.021

283. Hayden PJ An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT Curr. Res. Transl. Med. 2019 67 79 88 31182380 10.1016/j.retram.2019.05.002 Hayden, P. J. et al. An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT. Curr. Res. Transl. Med. 67 , 79–88 (2019). 31182380 10.1016/j.retram.2019.05.002

284. Pan X Xu J Jia X Research Progress Evaluating the Function and Mechanism of Anti-Tumor Peptides Cancer Manag. Res. 2020 12 397 409 10.2147/CMAR.S232708 32021452 PMC6970611 Pan, X., Xu, J. & Jia, X. Research Progress Evaluating the Function and Mechanism of Anti-Tumor Peptides. Cancer Manag. Res. 12 , 397–409 (2020). 32021452 10.2147/CMAR.S232708 PMC6970611

285. Karami Fath M Anti-cancer peptide-based therapeutic strategies in solid tumors Cell. Mol. Biol. Lett. 2022 27 33 10.1186/s11658-022-00332-w 35397496 PMC8994312 Karami Fath, M. et al. Anti-cancer peptide-based therapeutic strategies in solid tumors. Cell. Mol. Biol. Lett. 27 , 33 (2022). 35397496 10.1186/s11658-022-00332-w PMC8994312

286. Faraji N ApInAPDB: a database of apoptosis-inducing anticancer peptides Sci. Rep. 2022 12 21341 10.1038/s41598-022-25530-6 36494486 PMC9734560 Faraji, N. et al. ApInAPDB: a database of apoptosis-inducing anticancer peptides. Sci. Rep. 12 , 21341 (2022). 36494486 10.1038/s41598-022-25530-6 PMC9734560

287. Wu D Peptide-based cancer therapy: Opportunity and challenge Cancer Lett. 2014 351 13 22 10.1016/j.canlet.2014.05.002 24836189 Wu, D. et al. Peptide-based cancer therapy: Opportunity and challenge. Cancer Lett. 351 , 13–22 (2014). 24836189 10.1016/j.canlet.2014.05.002

288. Kordi M Antimicrobial peptides with anticancer activity: Today status, trends and their computational design Arch. Biochem. Biophys. 2023 733 109484 10.1016/j.abb.2022.109484 36473507 Kordi, M. et al. Antimicrobial peptides with anticancer activity: Today status, trends and their computational design. Arch. Biochem. Biophys. 733 , 109484 (2023). 36473507 10.1016/j.abb.2022.109484

289. Rady I Siddiqui IA Rady M Mukhtar H Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy Cancer Lett. 2017 402 16 31 10.1016/j.canlet.2017.05.010 28536009 PMC5682937 Rady, I., Siddiqui, I. A., Rady, M. & Mukhtar, H. Melittin, a major peptide component of bee venom, and its conjugates in cancer therapy. Cancer Lett. 402 , 16–31 (2017). 28536009 10.1016/j.canlet.2017.05.010 PMC5682937

290. Haug BE Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide J. Med. Chem. 2016 59 2918 2927 10.1021/acs.jmedchem.5b02025 26982623 Haug, B. E. et al. Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide. J. Med. Chem. 59 , 2918–2927 (2016). 26982623 10.1021/acs.jmedchem.5b02025

291. Camilio KA Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315 Cancer Immunol. Immunother. 2014 63 601 613 10.1007/s00262-014-1540-0 24676901 PMC4024132 Camilio, K. A. et al. Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315. Cancer Immunol. Immunother. 63 , 601–613 (2014). 24676901 10.1007/s00262-014-1540-0 PMC4024132

292. Wang K-r Antitumor effects, cell selectivity and structure–activity relationship of a novel antimicrobial peptide polybia-MPI Peptides 2008 29 963 968 10.1016/j.peptides.2008.01.015 18328599 Wang, K.-r et al. Antitumor effects, cell selectivity and structure–activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29 , 963–968 (2008). 18328599 10.1016/j.peptides.2008.01.015

293. Souza BM Structural and functional characterization of two novel peptide toxins isolated from the venom of the social wasp Polybia paulista Peptides 2005 26 2157 2164 10.1016/j.peptides.2005.04.026 16129513 Souza, B. M. et al. Structural and functional characterization of two novel peptide toxins isolated from the venom of the social wasp Polybia paulista. Peptides 26 , 2157–2164 (2005). 16129513 10.1016/j.peptides.2005.04.026

294. Wang K-r Novel mode of action of polybia-MPI, a novel antimicrobial peptide, in multi-drug resistant leukemic cells Cancer Lett. 2009 278 65 72 10.1016/j.canlet.2008.12.027 19233550 Wang, K.-r et al. Novel mode of action of polybia-MPI, a novel antimicrobial peptide, in multi-drug resistant leukemic cells. Cancer Lett. 278 , 65–72 (2009). 19233550 10.1016/j.canlet.2008.12.027

295. Kim SH Regulation of the HIF-1alpha stability by histone deacetylases Oncol. Rep. 2007 17 647 651 17273746 Kim, S. H. et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol. Rep. 17 , 647–651 (2007). 17273746

296. Jones P A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo J. Med. Chem. 2008 51 2350 2353 10.1021/jm800079s 18370373 Jones, P. et al. A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo. J. Med. Chem. 51 , 2350–2353 (2008). 18370373 10.1021/jm800079s

297. Ahn MY Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4 Int. J. Oncol. 2010 36 125 131 19956841 Ahn, M. Y. et al. Anti-tumor effect of apicidin on Ishikawa human endometrial cancer cells both in vitro and in vivo by blocking histone deacetylase 3 and 4. Int. J. Oncol. 36 , 125–131 (2010). 19956841

298. Wang J Advances in biosynthesis of peptide drugs: Technology and industrialization Biotechnol. J. 2024 19 e2300256 10.1002/biot.202300256 37884278 Wang, J. et al. Advances in biosynthesis of peptide drugs: Technology and industrialization. Biotechnol. J. 19 , e2300256 (2024). 37884278 10.1002/biot.202300256

299. Merrifield RB Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide J. Am. Chem. Soc. 1963 85 2149 2154 10.1021/ja00897a025 Merrifield, R. B. Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. J. Am. Chem. Soc. 85 , 2149–2154 (1963).

300. Sharma A Kumar A de la Torre BG Albericio F Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides Chem. Rev. 2022 122 13516 13546 10.1021/acs.chemrev.2c00132 35816287 Sharma, A., Kumar, A., de la Torre, B. G. & Albericio, F. Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides. Chem. Rev. 122 , 13516–13546 (2022). 35816287 10.1021/acs.chemrev.2c00132

301. Al Toma RS Brieke C Cryle MJ Süssmuth RD Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products Nat. Prod. Rep. 2015 32 1207 1235 10.1039/C5NP00025D 25940955 Al Toma, R. S., Brieke, C., Cryle, M. J. & Süssmuth, R. D. Structural aspects of phenylglycines, their biosynthesis and occurrence in peptide natural products. Nat. Prod. Rep. 32 , 1207–1235 (2015). 25940955 10.1039/c5np00025d

302. Lombó F Deciphering the biosynthesis pathway of the antitumor thiocoraline from a marine actinomycete and its expression in two streptomyces species ChemBioChem 2006 7 366 376 10.1002/cbic.200500325 16408310 Lombó, F. et al. Deciphering the biosynthesis pathway of the antitumor thiocoraline from a marine actinomycete and its expression in two streptomyces species. ChemBioChem 7 , 366–376 (2006). 16408310 10.1002/cbic.200500325

303. Praseuth AP Complete sequence of biosynthetic gene cluster responsible for producing triostin A and evaluation of quinomycin-type antibiotics from Streptomyces triostinicus Biotechnol. Prog. 2008 24 1226 1231 10.1002/btpr.34 19194935 Praseuth, A. P. et al. Complete sequence of biosynthetic gene cluster responsible for producing triostin A and evaluation of quinomycin-type antibiotics from Streptomyces triostinicus. Biotechnol. Prog. 24 , 1226–1231 (2008). 19194935 10.1002/btpr.34

304. Watanabe K Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli Nat. Chem. Biol. 2006 2 423 428 10.1038/nchembio803 16799553 Watanabe, K. et al. Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli. Nat. Chem. Biol. 2 , 423–428 (2006). 16799553 10.1038/nchembio803

305. Zolova OE Mady AS Garneau-Tsodikova S Recent developments in bisintercalator natural products Biopolymers 2010 93 777 790 10.1002/bip.21489 20578002 Zolova, O. E., Mady, A. S. & Garneau-Tsodikova, S. Recent developments in bisintercalator natural products. Biopolymers 93 , 777–790 (2010). 20578002 10.1002/bip.21489

306. Fields GB Noble RL Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids Int J. Pept. Protein Res. 1990 35 161 214 10.1111/j.1399-3011.1990.tb00939.x 2191922 Fields, G. B. & Noble, R. L. Solid phase peptide synthesis utilizing 9-fluorenylmethoxycarbonyl amino acids. Int J. Pept. Protein Res. 35 , 161–214 (1990). 2191922 10.1111/j.1399-3011.1990.tb00939.x

307. Mäde V Els-Heindl S Beck-Sickinger AG Automated solid-phase peptide synthesis to obtain therapeutic peptides Beilstein J. Org. Chem. 2014 10 1197 1212 10.3762/bjoc.10.118 24991269 PMC4077397 Mäde, V., Els-Heindl, S. & Beck-Sickinger, A. G. Automated solid-phase peptide synthesis to obtain therapeutic peptides. Beilstein J. Org. Chem. 10 , 1197–1212 (2014). 24991269 10.3762/bjoc.10.118 PMC4077397

308. Ramesh S Microreactors for peptide synthesis: looking through the eyes of twenty first century !!! Amino Acids 2014 46 2091 2104 10.1007/s00726-014-1776-1 24961648 Ramesh, S. et al. Microreactors for peptide synthesis: looking through the eyes of twenty first century !!! Amino Acids 46 , 2091–2104 (2014). 24961648 10.1007/s00726-014-1776-1

309. Vanier GS Microwave-assisted solid-phase peptide synthesis based on the Fmoc protecting group strategy (CEM) Methods Mol. Biol. 2013 1047 235 249 10.1007/978-1-62703-544-6_17 23943491 Vanier, G. S. Microwave-assisted solid-phase peptide synthesis based on the Fmoc protecting group strategy (CEM). Methods Mol. Biol. 1047 , 235–249 (2013). 23943491 10.1007/978-1-62703-544-6_17

310. Fuse S Mifune Y Nakamura H Tanaka H Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation Nat. Commun. 2016 7 13491 10.1038/ncomms13491 27892469 PMC5133696 Fuse, S., Mifune, Y., Nakamura, H. & Tanaka, H. Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation. Nat. Commun. 7 , 13491 (2016). 27892469 10.1038/ncomms13491 PMC5133696

311. Zhou R Synthesis and biological evaluation of Reniochalistatins A-E and a Reniochalistatin E analogue Chem. Med. Chem. 2018 13 2202 2207 10.1002/cmdc.201800529 30102451 Zhou, R. et al. Synthesis and biological evaluation of Reniochalistatins A-E and a Reniochalistatin E analogue. Chem. Med. Chem. 13 , 2202–2207 (2018). 30102451 10.1002/cmdc.201800529

312. Zhan KX Reniochalistatins A-E, cyclic peptides from the marine sponge Reniochalina stalagmitis J. Nat. Prod. 2014 77 2678 2684 10.1021/np5006778 25490132 Zhan, K. X. et al. Reniochalistatins A-E, cyclic peptides from the marine sponge Reniochalina stalagmitis. J. Nat. Prod. 77 , 2678–2684 (2014). 25490132 10.1021/np5006778

313. Luo H Synthesis of cyclic peptide reniochalistatin E and conformational isomers Chin. Chem. Lett. 2018 29 1143 1146 10.1016/j.cclet.2018.05.033 Luo, H. et al. Synthesis of cyclic peptide reniochalistatin E and conformational isomers. Chin. Chem. Lett. 29 , 1143–1146 (2018).

314. Tian W HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial–mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/β-catenin signaling activation Acta Pharm. Sin. B. 2021 11 1592 1606 10.1016/j.apsb.2021.03.040 34221870 PMC8245914 Tian, W. et al. HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial–mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/β-catenin signaling activation. Acta Pharm. Sin. B. 11 , 1592–1606 (2021). 34221870 10.1016/j.apsb.2021.03.040 PMC8245914

315. Tuguzbaeva G PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting α v integrin/FAK/Src signaling in oral squamous cell carcinoma cells Acta Pharm. Sin. B 2019 9 1163 1173 10.1016/j.apsb.2019.10.005 31867162 PMC6900557 Tuguzbaeva, G. et al. PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting α v integrin/FAK/Src signaling in oral squamous cell carcinoma cells. Acta Pharm. Sin. B 9 , 1163–1173 (2019). 31867162 10.1016/j.apsb.2019.10.005 PMC6900557

316. Yu S PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition Br. J. Pharm. 2018 175 3111 3130 10.1111/bph.14352 PMC6031886 29722931 Yu, S. et al. PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition. Br. J. Pharm. 175 , 3111–3130 (2018). 10.1111/bph.14352 PMC6031886 29722931

317. Lewis I Bruns C Synthesis of somatostatin analogues incorporating nucleo amino acids Tetrahedron 1994 50 7485 7494 10.1016/S0040-4020(01)90476-4 Lewis, I. & Bruns, C. Synthesis of somatostatin analogues incorporating nucleo amino acids. Tetrahedron 50 , 7485–7494 (1994).

318. Wang X-X Effects of octreotide on hepatic glycogenesis in rats with high fat diet-induced obesity Mol. Med. Report. 2017 16 109 118 10.3892/mmr.2017.6586 PMC5482138 28534956 Wang, X.-X. et al. Effects of octreotide on hepatic glycogenesis in rats with high fat diet-induced obesity. Mol. Med. Report. 16 , 109–118 (2017). 10.3892/mmr.2017.6586 PMC5482138 28534956

319. Sanyal AJ Octreotide and its effects on portal circulation Gastroenterology 2001 120 303 305 10.1053/gast.2001.21619 11208741 Sanyal, A. J. Octreotide and its effects on portal circulation. Gastroenterology 120 , 303–305 (2001). 11208741 10.1053/gast.2001.21619

320. Remuzzi G Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease PLoS One 2017 12 e0177934 10.1371/journal.pone.0177934 28542433 PMC5436842 Remuzzi, G. et al. Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease. PLoS One 12 , e0177934 (2017). 28542433 10.1371/journal.pone.0177934 PMC5436842

321. Kate McKeage SC Antona JWagstaff Octreotide long-acting release (LAR) a review of its use in the management of acromegaly Drugs 2003 22 2473 2499 10.2165/00003495-200363220-00014 14609359 Kate McKeage, S. C. & Antona, J. Wagstaff Octreotide long-acting release (LAR) a review of its use in the management of acromegaly. Drugs 22 , 2473–2499 (2003). 10.2165/00003495-200363220-00014 14609359

322. Borna RM Pharmacology of Octreotide: Clinical Implications for Anesthesiologists and Associated Risks Anesthesiol. Clin. 2017 35 327 339 10.1016/j.anclin.2017.01.021 28526153 Borna, R. M. et al. Pharmacology of Octreotide: Clinical Implications for Anesthesiologists and Associated Risks. Anesthesiol. Clin. 35 , 327–339 (2017). 28526153 10.1016/j.anclin.2017.01.021

323. Wolin EM The expanding role of somatostatin analogs in the management of neuroendocrine tumors Gastrointest. Cancer Res. 2012 5 161 168 23112884 PMC3481148 Wolin, E. M. The expanding role of somatostatin analogs in the management of neuroendocrine tumors. Gastrointest. Cancer Res. 5 , 161–168 (2012). 23112884 PMC3481148

324. Micale N Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design Med. Res. Rev. 2014 34 1001 1069 10.1002/med.21312 24585725 Micale, N. et al. Peptide‐Based Proteasome Inhibitors in Anticancer Drug Design. Med. Res. Rev. 34 , 1001–1069 (2014). 24585725 10.1002/med.21312

325. Robak P Robak T Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later Drugs RD 2019 19 73 92 10.1007/s40268-019-0269-9 PMC6544598 30993606 Robak, P. & Robak, T. Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later. Drugs RD 19 , 73–92 (2019). 10.1007/s40268-019-0269-9 PMC6544598 30993606

326. Hoy SM Motixafortide: First Approval Drugs 2023 83 1635 1643 10.1007/s40265-023-01962-w 37996648 Hoy, S. M. Motixafortide: First Approval. Drugs 83 , 1635–1643 (2023). 37996648 10.1007/s40265-023-01962-w

327. Choi W-T Drug Discovery Research Targeting the CXC Chemokine Receptor 4 (CXCR4) J. Med. Chem. 2011 55 977 994 10.1021/jm200568c 22085380 PMC3476736 Choi, W.-T. et al. Drug Discovery Research Targeting the CXC Chemokine Receptor 4 (CXCR4). J. Med. Chem. 55 , 977–994 (2011). 22085380 10.1021/jm200568c PMC3476736

328. Duan Q Zhang H Zheng J Zhang L Turning Cold into Hot: Firing up the Tumor Microenvironment Trends Cancer 2020 6 605 618 10.1016/j.trecan.2020.02.022 32610070 Duan, Q., Zhang, H., Zheng, J. & Zhang, L. Turning Cold into Hot: Firing up the Tumor Microenvironment. Trends Cancer 6 , 605–618 (2020). 32610070 10.1016/j.trecan.2020.02.022

329. Bonaventura P Cold Tumors: A Therapeutic Challenge for Immunotherapy Front. Immunol. 2019 10 168 10.3389/fimmu.2019.00168 30800125 PMC6376112 Bonaventura, P. et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy. Front. Immunol. 10 , 168 (2019). 30800125 10.3389/fimmu.2019.00168 PMC6376112

330. Tang Q Su Z Gu W Rustgi AK Mutant p53 on the Path to Metastasis Trends Cancer 2020 6 62 73 10.1016/j.trecan.2019.11.004 31952783 PMC7485681 Tang, Q., Su, Z., Gu, W. & Rustgi, A. K. Mutant p53 on the Path to Metastasis. Trends Cancer 6 , 62–73 (2020). 31952783 10.1016/j.trecan.2019.11.004 PMC7485681

331. Li C Systematic Mutational Analysis of Peptide Inhibition of the p53–MDM2/MDMX Interactions J. Mol. Biol. 2010 398 200 213 10.1016/j.jmb.2010.03.005 20226197 PMC2856455 Li, C. et al. Systematic Mutational Analysis of Peptide Inhibition of the p53–MDM2/MDMX Interactions. J. Mol. Biol. 398 , 200–213 (2010). 20226197 10.1016/j.jmb.2010.03.005 PMC2856455

332. Pazgier M Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX Proc. Natl Acad. Sci. USA 2009 106 4665 4670 10.1073/pnas.0900947106 19255450 PMC2660734 Pazgier, M. et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc. Natl Acad. Sci. USA 106 , 4665–4670 (2009). 19255450 10.1073/pnas.0900947106 PMC2660734

333. D’Aloisio V Dognini P Hutcheon GA Coxon CR PepTherDia: database and structural composition analysis of approved peptide therapeutics and diagnostics Drug Discov. Today 2021 26 1409 1419 10.1016/j.drudis.2021.02.019 33647438 D’Aloisio, V., Dognini, P., Hutcheon, G. A. & Coxon, C. R. PepTherDia: database and structural composition analysis of approved peptide therapeutics and diagnostics. Drug Discov. Today 26 , 1409–1419 (2021). 33647438 10.1016/j.drudis.2021.02.019

334. Hennrich U Benešová M [68Ga]Ga-DOTA-TOC: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging Pharmaceuticals 2020 13 38 10.3390/ph13030038 32138377 PMC7151717 Hennrich, U. & Benešová, M. [68Ga]Ga-DOTA-TOC: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging. Pharmaceuticals 13 , 38 (2020). 32138377 10.3390/ph13030038 PMC7151717

335. Hennrich U Eder M [68Ga]Ga-PSMA-11: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging of Prostate Cancer Pharmaceuticals 2021 14 713 10.3390/ph14080713 34451810 PMC8401928 Hennrich, U. & Eder, M. [68Ga]Ga-PSMA-11: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging of Prostate Cancer. Pharmaceuticals 14 , 713 (2021). 34451810 10.3390/ph14080713 PMC8401928

336. Heo Y-A Flotufolastat F 18: Diagnostic First Approval Mol. Diagn. Ther. 2023 27 631 636 10.1007/s40291-023-00665-y 37439946 Heo, Y.-A. Flotufolastat F 18: Diagnostic First Approval. Mol. Diagn. Ther. 27 , 631–636 (2023). 37439946 10.1007/s40291-023-00665-y

337. Joseph P Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors Circ. Res. 2017 121 677 694 10.1161/CIRCRESAHA.117.308903 28860318 Joseph, P. et al. Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors. Circ. Res. 121 , 677–694 (2017). 28860318 10.1161/CIRCRESAHA.117.308903

338. Mensah GA Fuster V Murray CJL Roth GA Global Burden of Cardiovascular Diseases and Risks, 1990-2022 J. Am. Coll. Cardiol. 2023 82 2350 2473 10.1016/j.jacc.2023.11.007 38092509 PMC7615984 Mensah, G. A., Fuster, V., Murray, C. J. L. & Roth, G. A. Global Burden of Cardiovascular Diseases and Risks, 1990-2022. J. Am. Coll. Cardiol. 82 , 2350–2473 (2023). 38092509 10.1016/j.jacc.2023.11.007 PMC7615984

339. Landmesser U From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases Eur. Heart J. 2020 41 3884 3899 10.1093/eurheartj/ehaa229 32350510 Landmesser, U. et al. From traditional pharmacological towards nucleic acid-based therapies for cardiovascular diseases. Eur. Heart J. 41 , 3884–3899 (2020). 32350510 10.1093/eurheartj/ehaa229

340. Kraus L Beavens B The Current Therapeutic Role of Chromatin Remodeling for the Prognosis and Treatment of Heart Failure Biomedicines 2023 11 579 10.3390/biomedicines11020579 36831115 PMC9953583 Kraus, L. & Beavens, B. The Current Therapeutic Role of Chromatin Remodeling for the Prognosis and Treatment of Heart Failure. Biomedicines 11 , 579 (2023). 36831115 10.3390/biomedicines11020579 PMC9953583

341. Cao DJ Epigenetic regulation and heart failure Expert Rev. Cardiovasc. Ther. 2014 12 1087 1098 10.1586/14779072.2014.942285 25047512 Cao, D. J. Epigenetic regulation and heart failure. Expert Rev. Cardiovasc. Ther. 12 , 1087–1098 (2014). 25047512 10.1586/14779072.2014.942285

342. Chaturvedi P Tyagi SC Epigenetic mechanisms underlying cardiac degeneration and regeneration Int. J. Cardiol. 2014 173 1 11 10.1016/j.ijcard.2014.02.008 24636549 PMC3982321 Chaturvedi, P. & Tyagi, S. C. Epigenetic mechanisms underlying cardiac degeneration and regeneration. Int. J. Cardiol. 173 , 1–11 (2014). 24636549 10.1016/j.ijcard.2014.02.008 PMC3982321

343. Xiao W Long non-coding RNA MIAT is involved in the regulation of pyroptosis in diabetic cardiomyopathy via targeting miR-214-3p iScience 2021 24 103518 10.1016/j.isci.2021.103518 34950859 PMC8671938 Xiao, W. et al. Long non-coding RNA MIAT is involved in the regulation of pyroptosis in diabetic cardiomyopathy via targeting miR-214-3p. iScience 24 , 103518 (2021). 34950859 10.1016/j.isci.2021.103518 PMC8671938

344. Wu F Full-length human GLP-1 receptor structure without orthosteric ligands Nat. Commun. 2020 11 1272 10.1038/s41467-020-14934-5 32152292 PMC7062719 Wu, F. et al. Full-length human GLP-1 receptor structure without orthosteric ligands. Nat. Commun. 11 , 1272 (2020). 32152292 10.1038/s41467-020-14934-5 PMC7062719

345. Wang JY GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach Front Endocrinol. (Lausanne) 2023 14 1085799 10.3389/fendo.2023.1085799 36843578 PMC9945324 Wang, J. Y. et al. GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach. Front Endocrinol. (Lausanne) 14 , 1085799 (2023). 36843578 10.3389/fendo.2023.1085799 PMC9945324

346. DeFronzo RA Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes Diabetes Care 2005 28 1092 1100 10.2337/diacare.28.5.1092 15855572 DeFronzo, R. A. et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28 , 1092–1100 (2005). 15855572 10.2337/diacare.28.5.1092

347. Xu D Potential Roles of Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) in Nondiabetic Populations Cardiovasc. Ther. 2022 2022 6820377 10.1155/2022/6820377 36474714 PMC9683988 Xu, D. et al. Potential Roles of Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs) in Nondiabetic Populations. Cardiovasc. Ther. 2022 , 6820377 (2022). 36474714 10.1155/2022/6820377 PMC9683988

348. Chen WR Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention Am. Heart J. 2015 170 845 854 10.1016/j.ahj.2015.07.014 26542491 Chen, W. R. et al. Effects of liraglutide on left ventricular function in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am. Heart J. 170 , 845–854 (2015). 26542491 10.1016/j.ahj.2015.07.014

349. Chen WR Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction Endocrine 2016 52 516 526 10.1007/s12020-015-0798-0 26573925 Chen, W. R. et al. Effects of liraglutide on left ventricular function in patients with non-ST-segment elevation myocardial infarction. Endocrine 52 , 516–526 (2016). 26573925 10.1007/s12020-015-0798-0

350. Wroge J Williams NT Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Cardiac Disorders Ann. Pharmacother. 2016 50 1041 1050 10.1177/1060028016663218 27531946 Wroge, J. & Williams, N. T. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Cardiac Disorders. Ann. Pharmacother. 50 , 1041–1050 (2016). 27531946 10.1177/1060028016663218

351. Ames RS Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14 Nature 1999 401 282 286 10.1038/45809 10499587 Ames, R. S. et al. Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401 , 282–286 (1999). 10499587 10.1038/45809

352. Douglas SA Congestive heart failure and expression of myocardial urotensin II Lancet 2002 359 1990 1997 10.1016/S0140-6736(02)08831-1 12076554 Douglas, S. A. et al. Congestive heart failure and expression of myocardial urotensin II. Lancet 359 , 1990–1997 (2002). 12076554 10.1016/S0140-6736(02)08831-1

353. Vergura R Urotensin II stimulates plasma extravasation in mice via UT receptor activation. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2004 370 347 352 10.1007/s00210-004-0991-9 15526105 Vergura, R. et al. Urotensin II stimulates plasma extravasation in mice via UT receptor activation. Naunyn-Schmiedeberg’s . Arch. Pharmacol. 370 , 347–352 (2004). 10.1007/s00210-004-0991-9 15526105

354. Zhao J Urantide attenuates myocardial damage in atherosclerotic rats by regulating the MAPK signalling pathway Life Sci. 2020 262 118551 10.1016/j.lfs.2020.118551 33038370 Zhao, J. et al. Urantide attenuates myocardial damage in atherosclerotic rats by regulating the MAPK signalling pathway. Life Sci. 262 , 118551 (2020). 33038370 10.1016/j.lfs.2020.118551

355. Wang Y Urantide improves the structure and function of right ventricle as determined by echocardiography in monocrotaline-induced pulmonary hypertension rat model Clin. Rheumatol. 2019 38 29 35 10.1007/s10067-018-3978-5 29362961 Wang, Y. et al. Urantide improves the structure and function of right ventricle as determined by echocardiography in monocrotaline-induced pulmonary hypertension rat model. Clin. Rheumatol. 38 , 29–35 (2019). 29362961 10.1007/s10067-018-3978-5

356. Elkayam U Nesiritide: a new drug for the treatment of decompensated heart failure J. Cardiovasc. Pharmacol. Ther. 2002 7 181 194 10.1177/107424840200700308 12232567 Elkayam, U. et al. Nesiritide: a new drug for the treatment of decompensated heart failure. J. Cardiovasc. Pharmacol. Ther. 7 , 181–194 (2002). 12232567 10.1177/107424840200700308

357. Burnett JC Jr Atrial Natriuretic Peptide, Heart Failure and the Heart as an Endocrine Organ Clin. Chem. 2019 65 1602 1603 10.1373/clinchem.2019.308106 31362934 PMC7055679 Burnett, J. C. Jr Atrial Natriuretic Peptide, Heart Failure and the Heart as an Endocrine Organ. Clin. Chem. 65 , 1602–1603 (2019). 31362934 10.1373/clinchem.2019.308106 PMC7055679

358. Kuwahara K The natriuretic peptide system in heart failure: Diagnostic and therapeutic implications Pharm. Ther. 2021 227 107863 10.1016/j.pharmthera.2021.107863 33894277 Kuwahara, K. The natriuretic peptide system in heart failure: Diagnostic and therapeutic implications. Pharm. Ther. 227 , 107863 (2021). 10.1016/j.pharmthera.2021.107863 33894277

359. Sackner-Bernstein JD Kowalski M Fox M Aaronson K Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials JAMA 2005 293 1900 1905 10.1001/jama.293.15.1900 15840865 Sackner-Bernstein, J. D., Kowalski, M., Fox, M. & Aaronson, K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 293 , 1900–1905 (2005). 15840865 10.1001/jama.293.15.1900

360. Hunt PJ Differing biological effects of equimolar atrial and brain natriuretic peptide infusions in normal man J. Clin. Endocrinol. Metab. 1996 81 3871 3876 8923831 10.1210/jcem.81.11.8923831 Hunt, P. J. et al. Differing biological effects of equimolar atrial and brain natriuretic peptide infusions in normal man. J. Clin. Endocrinol. Metab. 81 , 3871–3876 (1996). 8923831 10.1210/jcem.81.11.8923831

361. Wijeyaratne CN Moult PJ The effect of alpha human atrial natriuretic peptide on plasma volume and vascular permeability in normotensive subjects J. Clin. Endocrinol. Metab. 1993 76 343 346 8432776 10.1210/jcem.76.2.8432776 Wijeyaratne, C. N. & Moult, P. J. The effect of alpha human atrial natriuretic peptide on plasma volume and vascular permeability in normotensive subjects. J. Clin. Endocrinol. Metab. 76 , 343–346 (1993). 8432776 10.1210/jcem.76.2.8432776

362. Shah SJ Teerlink JR Nesiritide: a reappraisal of efficacy and safety Expert Opin. Pharmacother. 2007 8 361 369 10.1517/14656566.8.3.361 17266470 Shah, S. J. & Teerlink, J. R. Nesiritide: a reappraisal of efficacy and safety. Expert Opin. Pharmacother. 8 , 361–369 (2007). 17266470 10.1517/14656566.8.3.361

363. Iyengar S Feldman DS Trupp R Abraham WT Nesiritide for the treatment of congestive heart failure Expert Opin. Pharmacother. 2004 5 901 907 10.1517/14656566.5.4.901 15102572 Iyengar, S., Feldman, D. S., Trupp, R. & Abraham, W. T. Nesiritide for the treatment of congestive heart failure. Expert Opin. Pharmacother. 5 , 901–907 (2004). 15102572 10.1517/14656566.5.4.901

364. Tsutsui H Natriuretic peptides: role in the diagnosis and management of heart failure: a scientific statement from the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America and Japanese Heart Failure Society Eur. J. Heart Fail. 2023 25 616 631 10.1002/ejhf.2848 37098791 Tsutsui, H. et al. Natriuretic peptides: role in the diagnosis and management of heart failure: a scientific statement from the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America and Japanese Heart Failure Society. Eur. J. Heart Fail. 25 , 616–631 (2023). 37098791 10.1002/ejhf.2848

365. Ogiso M Effect of carperitide on in-hospital mortality of patients admitted for heart failure: propensity score analyses Heart Vessels 2017 32 916 925 10.1007/s00380-017-0952-0 28220240 Ogiso, M. et al. Effect of carperitide on in-hospital mortality of patients admitted for heart failure: propensity score analyses. Heart Vessels 32 , 916–925 (2017). 28220240 10.1007/s00380-017-0952-0

366. Ozawa T Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction J. Cardiol. 2015 66 232 238 10.1016/j.jjcc.2014.12.020 25722046 Ozawa, T. et al. Effects of human atrial natriuretic peptide on myocardial performance and energetics in heart failure due to previous myocardial infarction. J. Cardiol. 66 , 232–238 (2015). 25722046 10.1016/j.jjcc.2014.12.020

367. Matsue Y Carperitide Is Associated With Increased In-Hospital Mortality in Acute Heart Failure: A Propensity Score-Matched Analysis J. Card. Fail. 2015 21 859 864 10.1016/j.cardfail.2015.05.007 25999241 Matsue, Y. et al. Carperitide Is Associated With Increased In-Hospital Mortality in Acute Heart Failure: A Propensity Score-Matched Analysis. J. Card. Fail. 21 , 859–864 (2015). 25999241 10.1016/j.cardfail.2015.05.007

368. Inamoto M Predictors of a Good Diuretic Response and Administration Methods for Carperitide in Patients With Acute Heart Failure Clin. Ther. 2024 46 12 19 10.1016/j.clinthera.2023.10.006 37945501 Inamoto, M. et al. Predictors of a Good Diuretic Response and Administration Methods for Carperitide in Patients With Acute Heart Failure. Clin. Ther. 46 , 12–19 (2024). 37945501 10.1016/j.clinthera.2023.10.006

369. Asanuma H Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO Hypertens. Res. 2014 37 716 723 10.1038/hr.2014.70 24694647 Asanuma, H. et al. Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO. Hypertens. Res. 37 , 716–723 (2014). 24694647 10.1038/hr.2014.70

370. Carey RM Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association Hypertension 2018 72 e53 e90 10.1161/HYP.0000000000000084 30354828 PMC6530990 Carey, R. M. et al. Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association. Hypertension 72 , e53–e90 (2018). 30354828 10.1161/HYP.0000000000000084 PMC6530990

371. Desai AS Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program J. Am. Coll. Cardiol. 2007 50 1959 1966 10.1016/j.jacc.2007.07.067 17996561 Desai, A. S. et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J. Am. Coll. Cardiol. 50 , 1959–1966 (2007). 17996561 10.1016/j.jacc.2007.07.067

372. Yusuf S Telmisartan, ramipril, or both in patients at high risk for vascular events N. Engl. J. Med 2008 358 1547 1559 10.1056/NEJMoa0801317 18378520 Yusuf, S. et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N. Engl. J. Med 358 , 1547–1559 (2008). 18378520 10.1056/NEJMoa0801317

373. Lee SY Hur SJ Antihypertensive peptides from animal products, marine organisms, and plants Food Chem. 2017 228 506 517 10.1016/j.foodchem.2017.02.039 28317757 Lee, S. Y. & Hur, S. J. Antihypertensive peptides from animal products, marine organisms, and plants. Food Chem. 228 , 506–517 (2017). 28317757 10.1016/j.foodchem.2017.02.039

374. Fujita H Yoshikawa M LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein Immunopharmacology 1999 44 123 127 10.1016/S0162-3109(99)00118-6 10604535 Fujita, H. & Yoshikawa, M. LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein. Immunopharmacology 44 , 123–127 (1999). 10604535 10.1016/s0162-3109(99)00118-6

375. da Silva RL Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1-7) with selectivity for the C-terminal domain Bioorg. Chem. 2022 129 106204 10.1016/j.bioorg.2022.106204 36306699 da Silva, R. L. et al. Peptide inhibitors of angiotensin-I converting enzyme based on angiotensin (1-7) with selectivity for the C-terminal domain. Bioorg. Chem. 129 , 106204 (2022). 36306699 10.1016/j.bioorg.2022.106204

376. Neves AC Peptide identification in a salmon gelatin hydrolysate with antihypertensive, dipeptidyl peptidase IV inhibitory and antioxidant activities Food Res Int 2017 100 112 120 10.1016/j.foodres.2017.06.065 28873669 Neves, A. C. et al. Peptide identification in a salmon gelatin hydrolysate with antihypertensive, dipeptidyl peptidase IV inhibitory and antioxidant activities. Food Res Int 100 , 112–120 (2017). 28873669 10.1016/j.foodres.2017.06.065

377. Wang S Identification of novel angiotensin converting enzyme (ACE) inhibitory peptides from Pacific saury: In vivo antihypertensive effect and transport route Int. J. Biol. Macromol. 2024 254 127196 10.1016/j.ijbiomac.2023.127196 37793525 Wang, S. et al. Identification of novel angiotensin converting enzyme (ACE) inhibitory peptides from Pacific saury: In vivo antihypertensive effect and transport route. Int. J. Biol. Macromol. 254 , 127196 (2024). 37793525 10.1016/j.ijbiomac.2023.127196

378. Sorokina L Low Molecular Weight Peptide Fraction from Poultry Byproduct Hydrolysate Features Dual ACE-1 and DPP4 Inhibition ACS Food Sci. Technol. 2023 3 2219 2228 10.1021/acsfoodscitech.3c00417 Sorokina, L. et al. Low Molecular Weight Peptide Fraction from Poultry Byproduct Hydrolysate Features Dual ACE-1 and DPP4 Inhibition. ACS Food Sci. Technol. 3 , 2219–2228 (2023).

379. Phillips DR Scarborough RM Clinical pharmacology of eptifibatide Am. J. Cardiol. 1997 80 11b 20b 10.1016/S0002-9149(97)00572-9 9291241 Phillips, D. R. & Scarborough, R. M. Clinical pharmacology of eptifibatide. Am. J. Cardiol. 80 , 11b–20b (1997). 9291241 10.1016/s0002-9149(97)00572-9

380. Mohamed Abd El-Aziz T Garcia Soares A Stockand JD Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving Toxins 2019 11 564 10.3390/toxins11100564 31557973 PMC6832721 Mohamed Abd El-Aziz, T., Garcia Soares, A. & Stockand, J. D. Snake Venoms in Drug Discovery: Valuable Therapeutic Tools for Life Saving. Toxins 11 , 564 (2019). 31557973 10.3390/toxins11100564 PMC6832721

381. Huang J Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting J. Hematol. Oncol. 2019 12 26 10.1186/s13045-019-0709-6 30845955 PMC6407232 Huang, J. et al. Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting. J. Hematol. Oncol. 12 , 26 (2019). 30845955 10.1186/s13045-019-0709-6 PMC6407232

382. Gilchrist IC Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide Clin. Pharmacokinet. 2003 42 703 720 10.2165/00003088-200342080-00001 12846593 Gilchrist, I. C. Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide. Clin. Pharmacokinet. 42 , 703–720 (2003). 12846593 10.2165/00003088-200342080-00001

383. Fischer F Efficacy and Safety of Abbreviated Eptifibatide Treatment in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention Am. J. Cardiol. 2021 139 15 21 10.1016/j.amjcard.2020.09.054 33065082 Fischer, F. et al. Efficacy and Safety of Abbreviated Eptifibatide Treatment in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Am. J. Cardiol. 139 , 15–21 (2021). 33065082 10.1016/j.amjcard.2020.09.054

384. Gurm HS A comparison of abciximab and small-molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials Circ. Cardiovasc. Interv. 2009 2 230 236 10.1161/CIRCINTERVENTIONS.108.847996 20031720 Gurm, H. S. et al. A comparison of abciximab and small-molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials. Circ. Cardiovasc. Interv. 2 , 230–236 (2009). 20031720 10.1161/CIRCINTERVENTIONS.108.847996

385. Cannon CP Oral glycoprotein IIb/IIIa inhibition-great idea, but it didn’t work Am. J. Med. 2002 112 673 675 10.1016/S0002-9343(02)01146-4 12034420 Cannon, C. P. Oral glycoprotein IIb/IIIa inhibition-great idea, but it didn’t work. Am. J. Med. 112 , 673–675 (2002). 12034420 10.1016/s0002-9343(02)01146-4

386. Newby LK The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events Am. J. Med. 2002 112 647 658 10.1016/S0002-9343(02)01106-3 12034415 Newby, L. K. et al. The failure of orally administered glycoprotein IIb/IIIa inhibitors to prevent recurrent cardiac events. Am. J. Med. 112 , 647–658 (2002). 12034415 10.1016/s0002-9343(02)01106-3

387. Britsch S The neuregulin-I/ErbB signaling system in development and disease Adv. Anat. Embryol. Cell Biol. 2007 190 1 65 17432114 Britsch, S. The neuregulin-I/ErbB signaling system in development and disease. Adv. Anat. Embryol. Cell Biol. 190 , 1–65 (2007). 17432114

388. Geissler A Ryzhov S Sawyer DB Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease Clin. Sci. (Lond.) 2020 134 2623 2643 10.1042/CS20200230 33063822 PMC7557502 Geissler, A., Ryzhov, S. & Sawyer, D. B. Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease. Clin. Sci. (Lond.) 134 , 2623–2643 (2020). 33063822 10.1042/CS20200230 PMC7557502

389. Xu J Safety, Tolerability, and Pharmacokinetics of Recombinant Human Neuregulin-1 in Healthy Chinese Subjects Am. J. Cardiovasc. Drugs 2023 23 419 428 10.1007/s40256-023-00585-6 37204676 PMC10328871 Xu, J. et al. Safety, Tolerability, and Pharmacokinetics of Recombinant Human Neuregulin-1 in Healthy Chinese Subjects. Am. J. Cardiovasc. Drugs 23 , 419–428 (2023). 37204676 10.1007/s40256-023-00585-6 PMC10328871

390. Cooper MA Shlaes D Fix the antibiotics pipeline Nature 2011 472 32 10.1038/472032a 21475175 Cooper, M. A. & Shlaes, D. Fix the antibiotics pipeline. Nature 472 , 32 (2011). 21475175 10.1038/472032a

391. Chen CH Lu TK Development and Challenges of Antimicrobial Peptides for Therapeutic Applications Antibiotics (Basel). 2020 9 e24 10.3390/antibiotics9010024 PMC7168295 31941022 Chen, C. H. & Lu, T. K. Development and Challenges of Antimicrobial Peptides for Therapeutic Applications. Antibiotics (Basel). 9 , e24 (2020). 10.3390/antibiotics9010024 PMC7168295 31941022

392. Wang J Antimicrobial peptides: Promising alternatives in the post feeding antibiotic era Med. Res. Rev. 2019 39 831 859 10.1002/med.21542 30353555 Wang, J. et al. Antimicrobial peptides: Promising alternatives in the post feeding antibiotic era. Med. Res. Rev. 39 , 831–859 (2019). 30353555 10.1002/med.21542

393. Hancock RE Sahl HG Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies Nat. Biotechnol. 2006 24 1551 1557 10.1038/nbt1267 17160061 Hancock, R. E. & Sahl, H. G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 24 , 1551–1557 (2006). 17160061 10.1038/nbt1267

394. Pasupuleti M Schmidtchen A Malmsten M Antimicrobial peptides: key components of the innate immune system Crit. Rev. Biotechnol. 2012 32 143 171 10.3109/07388551.2011.594423 22074402 Pasupuleti, M., Schmidtchen, A. & Malmsten, M. Antimicrobial peptides: key components of the innate immune system. Crit. Rev. Biotechnol. 32 , 143–171 (2012). 22074402 10.3109/07388551.2011.594423

395. Takahashi D Shukla SK Prakash O Zhang G Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity Biochimie 2010 92 1236 1241 10.1016/j.biochi.2010.02.023 20188791 Takahashi, D., Shukla, S. K., Prakash, O. & Zhang, G. Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity. Biochimie 92 , 1236–1241 (2010). 20188791 10.1016/j.biochi.2010.02.023

396. Klüver E Structure-activity relation of human beta-defensin 3: influence of disulfide bonds and cysteine substitution on antimicrobial activity and cytotoxicity Biochemistry 2005 44 9804 9816 10.1021/bi050272k 16008365 Klüver, E. et al. Structure-activity relation of human beta-defensin 3: influence of disulfide bonds and cysteine substitution on antimicrobial activity and cytotoxicity. Biochemistry 44 , 9804–9816 (2005). 16008365 10.1021/bi050272k

397. Chan DI Prenner EJ Vogel HJ Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action Biochim Biophys. Acta 2006 1758 1184 1202 10.1016/j.bbamem.2006.04.006 16756942 Chan, D. I., Prenner, E. J. & Vogel, H. J. Tryptophan- and arginine-rich antimicrobial peptides: structures and mechanisms of action. Biochim Biophys. Acta 1758 , 1184–1202 (2006). 16756942 10.1016/j.bbamem.2006.04.006

398. Mookherjee N Anderson MA Haagsman HP Davidson DJ Antimicrobial host defence peptides: functions and clinical potential Nat. Rev. Drug Discov. 2020 19 311 332 10.1038/s41573-019-0058-8 32107480 Mookherjee, N., Anderson, M. A., Haagsman, H. P. & Davidson, D. J. Antimicrobial host defence peptides: functions and clinical potential. Nat. Rev. Drug Discov. 19 , 311–332 (2020). 32107480 10.1038/s41573-019-0058-8

399. Ismail NO Antimicrobial function of short amidated peptide fragments from the tick-derived OsDef2 defensin J. Pept. Sci. 2019 25 e3223 10.1002/psc.3223 31713951 Ismail, N. O. et al. Antimicrobial function of short amidated peptide fragments from the tick-derived OsDef2 defensin. J. Pept. Sci. 25 , e3223 (2019). 31713951 10.1002/psc.3223

400. Irazazabal LN Fast and potent bactericidal membrane lytic activity of PaDBS1R1, a novel cationic antimicrobial peptide Biochim Biophys. Acta Biomembr. 2019 1861 178 190 10.1016/j.bbamem.2018.08.001 30463701 Irazazabal, L. N. et al. Fast and potent bactericidal membrane lytic activity of PaDBS1R1, a novel cationic antimicrobial peptide. Biochim Biophys. Acta Biomembr. 1861 , 178–190 (2019). 30463701 10.1016/j.bbamem.2018.08.001

401. Giovati L Ciociola T Magliani W Conti S Antimicrobial peptides with antiprotozoal activity: current state and future perspectives Future Med. Chem. 2018 10 2569 2572 10.4155/fmc-2018-0460 30499691 Giovati, L., Ciociola, T., Magliani, W. & Conti, S. Antimicrobial peptides with antiprotozoal activity: current state and future perspectives. Future Med. Chem. 10 , 2569–2572 (2018). 30499691 10.4155/fmc-2018-0460

402. Brice DC Diamond G Antiviral Activities of Human Host Defense Peptides Curr. Med. Chem. 2020 27 1420 1443 10.2174/0929867326666190805151654 31385762 PMC9008596 Brice, D. C. & Diamond, G. Antiviral Activities of Human Host Defense Peptides. Curr. Med. Chem. 27 , 1420–1443 (2020). 31385762 10.2174/0929867326666190805151654 PMC9008596

403. Fernández de Ullivarri M Arbulu S Garcia-Gutierrez E Cotter PD Antifungal Peptides as Therapeutic Agents Front Cell Infect. Microbiol 2020 10 105 10.3389/fcimb.2020.00105 32257965 PMC7089922 Fernández de Ullivarri, M., Arbulu, S., Garcia-Gutierrez, E. & Cotter, P. D. Antifungal Peptides as Therapeutic Agents. Front Cell Infect. Microbiol 10 , 105 (2020). 32257965 10.3389/fcimb.2020.00105 PMC7089922

404. Aoki W Ueda M Characterization of Antimicrobial Peptides toward the Development of Novel Antibiotics Pharmaceuticals 2013 6 1055 1081 10.3390/ph6081055 24276381 PMC3817730 Aoki, W. & Ueda, M. Characterization of Antimicrobial Peptides toward the Development of Novel Antibiotics. Pharmaceuticals 6 , 1055–1081 (2013). 24276381 10.3390/ph6081055 PMC3817730

405. Zaiou M Multifunctional antimicrobial peptides: therapeutic targets in several human diseases J. Mol. Med. (Berl.) 2007 85 317 329 10.1007/s00109-006-0143-4 17216206 Zaiou, M. Multifunctional antimicrobial peptides: therapeutic targets in several human diseases. J. Mol. Med. (Berl.) 85 , 317–329 (2007). 17216206 10.1007/s00109-006-0143-4

406. Yount NY Yeaman MR Emerging themes and therapeutic prospects for anti-infective peptides Annu Rev. Pharm. Toxicol. 2012 52 337 360 10.1146/annurev-pharmtox-010611-134535 22235859 Yount, N. Y. & Yeaman, M. R. Emerging themes and therapeutic prospects for anti-infective peptides. Annu Rev. Pharm. Toxicol. 52 , 337–360 (2012). 10.1146/annurev-pharmtox-010611-134535 22235859

407. Baba MS In vivo antimalarial activity of the endophytic actinobacteria, Streptomyces SUK 10 J. Microbiol. 2015 53 847 855 10.1007/s12275-015-5076-6 26626355 Baba, M. S. et al. In vivo antimalarial activity of the endophytic actinobacteria, Streptomyces SUK 10. J. Microbiol. 53 , 847–855 (2015). 26626355 10.1007/s12275-015-5076-6

408. Toke O Antimicrobial peptides: new candidates in the fight against bacterial infections Biopolymers 2005 80 717 735 10.1002/bip.20286 15880793 Toke, O. Antimicrobial peptides: new candidates in the fight against bacterial infections. Biopolymers 80 , 717–735 (2005). 15880793 10.1002/bip.20286

409. Zhang QY Antimicrobial peptides: mechanism of action, activity and clinical potential Mil. Med. Res. 2021 8 48 34496967 10.1186/s40779-021-00343-2 PMC8425997 Zhang, Q. Y. et al. Antimicrobial peptides: mechanism of action, activity and clinical potential. Mil. Med. Res. 8 , 48 (2021). 34496967 10.1186/s40779-021-00343-2 PMC8425997

410. Kang HK Kim C Seo CH Park Y The therapeutic applications of antimicrobial peptides (AMPs): a patent review J. Microbiol. 2017 55 1 12 10.1007/s12275-017-6452-1 28035594 Kang, H. K., Kim, C., Seo, C. H. & Park, Y. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J. Microbiol. 55 , 1–12 (2017). 28035594 10.1007/s12275-017-6452-1

411. Rončević T Puizina J Tossi A Antimicrobial Peptides as Anti-Infective Agents in Pre-Post-Antibiotic Era? Int. J. Mol. Sci. 2019 20 5713 10.3390/ijms20225713 31739573 PMC6887943 Rončević, T., Puizina, J. & Tossi, A. Antimicrobial Peptides as Anti-Infective Agents in Pre-Post-Antibiotic Era? Int. J. Mol. Sci. 20 , 5713 (2019). 31739573 10.3390/ijms20225713 PMC6887943

412. Cudic M Otvos L Jr Intracellular targets of antibacterial peptides Curr. Drug Targets 2002 3 101 106 10.2174/1389450024605445 11958294 Cudic, M. & Otvos, L. Jr Intracellular targets of antibacterial peptides. Curr. Drug Targets 3 , 101–106 (2002). 11958294 10.2174/1389450024605445

413. Epand RM Vogel HJ Diversity of antimicrobial peptides and their mechanisms of action Biochim Biophys. Acta 1999 1462 11 28 10.1016/S0005-2736(99)00198-4 10590300 Epand, R. M. & Vogel, H. J. Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys. Acta 1462 , 11–28 (1999). 10590300 10.1016/s0005-2736(99)00198-4

414. Pader V Edwards AM Daptomycin: new insights into an antibiotic of last resort Future Microbiol 2017 12 461 464 10.2217/fmb-2017-0034 28481142 Pader, V. & Edwards, A. M. Daptomycin: new insights into an antibiotic of last resort. Future Microbiol 12 , 461–464 (2017). 28481142 10.2217/fmb-2017-0034

415. Heidary M Daptomycin J. Antimicrob. Chemother. 2018 73 1 11 10.1093/jac/dkx349 29059358 Heidary, M. et al. Daptomycin. J. Antimicrob. Chemother. 73 , 1–11 (2018). 29059358 10.1093/jac/dkx349

416. Tascini C Statins during daptomycin therapy: to give or not to give? Minerva Anestesiol. 2019 85 689 690 10.23736/S0375-9393.18.13393-1 30621379 Tascini, C. et al. Statins during daptomycin therapy: to give or not to give? Minerva Anestesiol. 85 , 689–690 (2019). 30621379 10.23736/S0375-9393.18.13393-1

417. Taylor SD Palmer M The action mechanism of daptomycin Bioorg. Med Chem. 2016 24 6253 6268 10.1016/j.bmc.2016.05.052 27288182 Taylor, S. D. & Palmer, M. The action mechanism of daptomycin. Bioorg. Med Chem. 24 , 6253–6268 (2016). 27288182 10.1016/j.bmc.2016.05.052

418. Daley P Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial J. Antimicrob. Chemother. 2017 72 3462 3470 10.1093/jac/dkx299 28961905 Daley, P. et al. Surotomycin versus vancomycin in adults with Clostridium difficile infection: primary clinical outcomes from the second pivotal, randomized, double-blind, Phase 3 trial. J. Antimicrob. Chemother. 72 , 3462–3470 (2017). 28961905 10.1093/jac/dkx299

419. Chandorkar G Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers BMC Pharm. Toxicol. 2017 18 24 10.1186/s40360-017-0123-z PMC5368910 28347318 Chandorkar, G. et al. Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers. BMC Pharm. Toxicol. 18 , 24 (2017). 10.1186/s40360-017-0123-z PMC5368910 28347318

420. Cannon K Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection J. Antimicrob. Chemother. 2017 72 3453 3461 10.1093/jac/dkx318 28927227 Cannon, K. et al. Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection. J. Antimicrob. Chemother. 72 , 3453–3461 (2017). 28927227 10.1093/jac/dkx318

421. Ramdeen S Boucher HW Dalbavancin for the treatment of acute bacterial skin and skin structure infections Expert Opin. Pharmacother. 2015 16 2073 2081 10.1517/14656566.2015.1075508 26239321 PMC4600683 Ramdeen, S. & Boucher, H. W. Dalbavancin for the treatment of acute bacterial skin and skin structure infections. Expert Opin. Pharmacother. 16 , 2073–2081 (2015). 26239321 10.1517/14656566.2015.1075508 PMC4600683

422. Garnock-Jones KP Single-Dose Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections Drugs 2017 77 75 83 10.1007/s40265-016-0666-0 27988870 Garnock-Jones, K. P. Single-Dose Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections. Drugs 77 , 75–83 (2017). 27988870 10.1007/s40265-016-0666-0

423. Corey GR Single-dose oritavancin in the treatment of acute bacterial skin infections N. Engl. J. Med 2014 370 2180 2190 10.1056/NEJMoa1310422 24897083 Corey, G. R. et al. Single-dose oritavancin in the treatment of acute bacterial skin infections. N. Engl. J. Med 370 , 2180–2190 (2014). 24897083 10.1056/NEJMoa1310422

424. Corey GR Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study Clin. Infect. Dis. 2015 60 254 262 10.1093/cid/ciu778 25294250 Corey, G. R. et al. Single-dose oritavancin versus 7-10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. Clin. Infect. Dis. 60 , 254–262 (2015). 25294250 10.1093/cid/ciu778

425. Lin G Pankuch G Appelbaum PC Kosowska-Shick K Antistaphylococcal activity of oritavancin and its synergistic effect in combination with other antimicrobial agents Antimicrob. Agents Chemother. 2014 58 6251 6254 10.1128/AAC.02932-14 25022588 PMC4187905 Lin, G., Pankuch, G., Appelbaum, P. C. & Kosowska-Shick, K. Antistaphylococcal activity of oritavancin and its synergistic effect in combination with other antimicrobial agents. Antimicrob. Agents Chemother. 58 , 6251–6254 (2014). 25022588 10.1128/AAC.02932-14 PMC4187905

426. Syed YY Rezafungin: First Approval Drugs 2023 83 833 840 10.1007/s40265-023-01891-8 37212966 Syed, Y. Y. Rezafungin: First Approval. Drugs 83 , 833–840 (2023). 37212966 10.1007/s40265-023-01891-8

427. Ham YY Lewis JS 2nd Thompson GR 3rd Rezafungin: a novel antifungal for the treatment of invasive candidiasis Future Microbiol. 2021 16 27 36 10.2217/fmb-2020-0217 33438477 Ham, Y. Y., Lewis, J. S. 2nd & Thompson, G. R. 3rd Rezafungin: a novel antifungal for the treatment of invasive candidiasis. Future Microbiol. 16 , 27–36 (2021). 33438477 10.2217/fmb-2020-0217

428. Lepak AJ Zhao M Andes DR Determination of Pharmacodynamic Target Exposures for Rezafungin against Candida tropicalis and Candida dubliniensis in the Neutropenic Mouse Disseminated Candidiasis Model Antimicrob. Agents Chemother. 2019 63 e01556 01519 10.1128/AAC.01556-19 31481440 PMC6811416 Lepak, A. J., Zhao, M. & Andes, D. R. Determination of Pharmacodynamic Target Exposures for Rezafungin against Candida tropicalis and Candida dubliniensis in the Neutropenic Mouse Disseminated Candidiasis Model. Antimicrob. Agents Chemother. 63 , e01556–01519 (2019). 31481440 10.1128/AAC.01556-19 PMC6811416

429. Wei Y Efficacy and Safety of PL-5 (Peceleganan) Spray for Wound Infections: A Phase IIb Randomized Clinical Trial Ann. Surg. 2023 277 43 49 10.1097/SLA.0000000000005508 35781462 PMC9762708 Wei, Y. et al. Efficacy and Safety of PL-5 (Peceleganan) Spray for Wound Infections: A Phase IIb Randomized Clinical Trial. Ann. Surg. 277 , 43–49 (2023). 35781462 10.1097/SLA.0000000000005508 PMC9762708

430. Atkinson DJ Naysmith BJ Furkert DP Brimble MA Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis Beilstein J. Org. Chem. 2016 12 2325 2342 10.3762/bjoc.12.226 28144300 PMC5238550 Atkinson, D. J., Naysmith, B. J., Furkert, D. P. & Brimble, M. A. Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis. Beilstein J. Org. Chem. 12 , 2325–2342 (2016). 28144300 10.3762/bjoc.12.226 PMC5238550

431. Breukink E de Kruijff B Lipid II as a target for antibiotics Nat. Rev. Drug Discov. 2006 5 321 332 10.1038/nrd2004 16531990 Breukink, E. & de Kruijff, B. Lipid II as a target for antibiotics. Nat. Rev. Drug Discov. 5 , 321–332 (2006). 16531990 10.1038/nrd2004

432. Shukla R Teixobactin kills bacteria by a two-pronged attack on the cell envelope Nature 2022 608 390 396 10.1038/s41586-022-05019-y 35922513 PMC9365693 Shukla, R. et al. Teixobactin kills bacteria by a two-pronged attack on the cell envelope. Nature 608 , 390–396 (2022). 35922513 10.1038/s41586-022-05019-y PMC9365693

433. Parmar A Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding Chem. Sci. 2017 8 8183 8192 10.1039/C7SC03241B 29568465 PMC5855875 Parmar, A. et al. Teixobactin analogues reveal enduracididine to be non-essential for highly potent antibacterial activity and lipid II binding. Chem. Sci. 8 , 8183–8192 (2017). 29568465 10.1039/c7sc03241b PMC5855875

434. Münch D Sahl HG Structural variations of the cell wall precursor lipid II in Gram-positive bacteria - Impact on binding and efficacy of antimicrobial peptides Biochim Biophys. Acta 2015 1848 3062 3071 10.1016/j.bbamem.2015.04.014 25934055 Münch, D. & Sahl, H. G. Structural variations of the cell wall precursor lipid II in Gram-positive bacteria - Impact on binding and efficacy of antimicrobial peptides. Biochim Biophys. Acta 1848 , 3062–3071 (2015). 25934055 10.1016/j.bbamem.2015.04.014

435. Beringer PM Rhesus θ-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa J. Antimicrob. Chemother. 2016 71 181 188 10.1093/jac/dkv301 26433781 PMC5007590 Beringer, P. M. et al. Rhesus θ-defensin-1 (RTD-1) exhibits in vitro and in vivo activity against cystic fibrosis strains of Pseudomonas aeruginosa. J. Antimicrob. Chemother. 71 , 181–188 (2016). 26433781 10.1093/jac/dkv301 PMC5007590

436. Tai KP Microbicidal effects of α- and θ-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa Innate Immun. 2015 21 17 29 10.1177/1753425913514784 24345876 PMC4062604 Tai, K. P. et al. Microbicidal effects of α- and θ-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa. Innate Immun. 21 , 17–29 (2015). 24345876 10.1177/1753425913514784 PMC4062604

437. Deslouches B Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications Antimicrob. Agents Chemother. 2005 49 3208 3216 10.1128/AAC.49.8.3208-3216.2005 16048927 PMC1196285 Deslouches, B. et al. Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications. Antimicrob. Agents Chemother. 49 , 3208–3216 (2005). 16048927 10.1128/AAC.49.8.3208-3216.2005 PMC1196285

438. Scoffone VC New Antimicrobial Strategies to Treat Multi-Drug Resistant Infections Caused by Gram-Negatives in Cystic Fibrosis Antibiotics (Basel) 2024 13 71 10.3390/antibiotics13010071 38247630 PMC10812592 Scoffone, V. C. et al. New Antimicrobial Strategies to Treat Multi-Drug Resistant Infections Caused by Gram-Negatives in Cystic Fibrosis. Antibiotics (Basel) 13 , 71 (2024). 38247630 10.3390/antibiotics13010071 PMC10812592

439. Chen C Deslouches B Montelaro RC Di YP Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia Clin. Microbiol Infect. 2018 24 547.e541 547.e548 10.1016/j.cmi.2017.08.029 PMC5835169 28882728 Chen, C., Deslouches, B., Montelaro, R. C. & Di, Y. P. Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia. Clin. Microbiol Infect. 24 , 547.e541–547.e548 (2018). 10.1016/j.cmi.2017.08.029 PMC5835169 28882728

440. Elsalem L Khasawneh A Al Sheboul S WLBU2 Antimicrobial Peptide as a Potential Therapeutic for Treatment of Resistant Bacterial Turk. J. Pharm. Sci. 2022 19 110 116 10.4274/tjps.galenos.2020.43078 35227034 PMC8892561 Elsalem, L., Khasawneh, A. & Al Sheboul, S. WLBU2 Antimicrobial Peptide as a Potential Therapeutic for Treatment of Resistant Bacterial. Turk. J. Pharm. Sci. 19 , 110–116 (2022). 35227034 10.4274/tjps.galenos.2020.43078 PMC8892561

441. Fung TS Liu DX Human Coronavirus: Host-Pathogen Interaction Annu. Rev. Microbiol. 2019 73 529 557 10.1146/annurev-micro-020518-115759 31226023 Fung, T. S. & Liu, D. X. Human Coronavirus: Host-Pathogen Interaction. Annu. Rev. Microbiol. 73 , 529–557 (2019). 31226023 10.1146/annurev-micro-020518-115759

442. de Wit E van Doremalen N Falzarano D Munster VJ SARS and MERS: recent insights into emerging coronaviruses Nat. Rev. Microbiol. 2016 14 523 534 10.1038/nrmicro.2016.81 27344959 PMC7097822 de Wit, E., van Doremalen, N., Falzarano, D. & Munster, V. J. SARS and MERS: recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 14 , 523–534 (2016). 27344959 10.1038/nrmicro.2016.81 PMC7097822

443. Han Y-J Advances and challenges in the prevention and treatment of COVID-19 Int. J. Med. Sci. 2020 17 1803 1810 10.7150/ijms.47836 32714083 PMC7378666 Han, Y.-J. et al. Advances and challenges in the prevention and treatment of COVID-19. Int. J. Med. Sci. 17 , 1803–1810 (2020). 32714083 10.7150/ijms.47836 PMC7378666

444. Nepali K Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal J. Biomed. Sci. 2022 29 65 10.1186/s12929-022-00847-6 36064696 PMC9444709 Nepali, K. et al. Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal. J. Biomed. Sci. 29 , 65 (2022). 36064696 10.1186/s12929-022-00847-6 PMC9444709

445. Lu L Su S Yang H Jiang S Antivirals with common targets against highly pathogenic viruses Cell 2021 184 1604 1620 10.1016/j.cell.2021.02.013 33740455 Lu, L., Su, S., Yang, H. & Jiang, S. Antivirals with common targets against highly pathogenic viruses. Cell 184 , 1604–1620 (2021). 33740455 10.1016/j.cell.2021.02.013

446. Xia S A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike Sci. Adv. 2019 5 eaav4580 10.1126/sciadv.aav4580 30989115 PMC6457931 Xia, S. et al. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci. Adv. 5 , eaav4580 (2019). 30989115 10.1126/sciadv.aav4580 PMC6457931

447. Gallagher TM Buchmeier MJ Coronavirus Spike Proteins in Viral Entry and Pathogenesis Virology 2001 279 371 374 10.1006/viro.2000.0757 11162792 PMC7133764 Gallagher, T. M. & Buchmeier, M. J. Coronavirus Spike Proteins in Viral Entry and Pathogenesis. Virology 279 , 371–374 (2001). 11162792 10.1006/viro.2000.0757 PMC7133764

448. Wrapp D Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 2020 1367 1260 1263 10.1126/science.abb2507 PMC7164637 32075877 Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 1367 , 1260–1263 (2020). 10.1126/science.abb2507 PMC7164637 32075877

449. Zhou P A pneumonia outbreak associated with a new coronavirus of probable bat origin Nature 2020 579 270 273 10.1038/s41586-020-2012-7 32015507 PMC7095418 Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579 , 270–273 (2020). 32015507 10.1038/s41586-020-2012-7 PMC7095418

450. Xia S Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein Virus Res 2014 194 200 210 10.1016/j.virusres.2014.10.007 25451066 PMC7114414 Xia, S. et al. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res 194 , 200–210 (2014). 25451066 10.1016/j.virusres.2014.10.007 PMC7114414

451. Li F Structure, Function, and Evolution of Coronavirus Spike Proteins Annu. Rev. Virol. 2016 3 237 261 10.1146/annurev-virology-110615-042301 27578435 PMC5457962 Li, F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol. 3 , 237–261 (2016). 27578435 10.1146/annurev-virology-110615-042301 PMC5457962

452. Chen Y Liu Q Guo D Emerging coronaviruses: Genome structure, replication, and pathogenesis J. Med. Virol. 2020 92 418 423 10.1002/jmv.25681 31967327 PMC7167049 Chen, Y., Liu, Q. & Guo, D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J. Med. Virol. 92 , 418–423 (2020). 31967327 10.1002/jmv.25681 PMC7167049

453. Gil C COVID-19: Drug Targets and Potential Treatments J. Med. Chem. 2020 63 12359 12386 10.1021/acs.jmedchem.0c00606 32511912 Gil, C. et al. COVID-19: Drug Targets and Potential Treatments. J. Med. Chem. 63 , 12359–12386 (2020). 32511912 10.1021/acs.jmedchem.0c00606

454. Lamb YN Nirmatrelvir Plus Ritonavir: First Approval Drugs 2022 82 585 591 10.1007/s40265-022-01692-5 35305258 PMC8933659 Lamb, Y. N. Nirmatrelvir Plus Ritonavir: First Approval. Drugs 82 , 585–591 (2022). 35305258 10.1007/s40265-022-01692-5 PMC8933659

455. Reina J Iglesias C Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination Rev. Esp. Quimioter. 2022 35 236 240 10.37201/req/002.2022 35183067 PMC9134883 Reina, J. & Iglesias, C. Nirmatrelvir plus ritonavir (Paxlovid) a potent SARS-CoV-2 3CLpro protease inhibitor combination. Rev. Esp. Quimioter. 35 , 236–240 (2022). 35183067 10.37201/req/002.2022 PMC9134883

456. Wan K Patient Centric Microsampling to Support Paxlovid Clinical Development: Bridging and Implementation Clin. Pharmacol. Ther. 2023 115 42 51 10.1002/cpt.3025 37597239 Wan, K. et al. Patient Centric Microsampling to Support Paxlovid Clinical Development: Bridging and Implementation. Clin. Pharmacol. Ther. 115 , 42–51 (2023). 37597239 10.1002/cpt.3025

457. Heskin J Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management Lancet 2022 399 21 22 10.1016/S0140-6736(21)02657-X 34973713 PMC8718360 Heskin, J. et al. Caution required with use of ritonavir-boosted PF-07321332 in COVID-19 management. Lancet 399 , 21–22 (2022). 34973713 10.1016/S0140-6736(21)02657-X PMC8718360

458. Zhao Y Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332 Protein Cell 2022 13 689 693 10.1007/s13238-021-00883-2 34687004 PMC8533666 Zhao, Y. et al. Crystal structure of SARS-CoV-2 main protease in complex with protease inhibitor PF-07321332. Protein Cell 13 , 689–693 (2022). 34687004 10.1007/s13238-021-00883-2 PMC8533666

459. Hammond J Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 N. Engl. J. Med. 2022 386 1397 1408 10.1056/NEJMoa2118542 35172054 PMC8908851 Hammond, J. et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N. Engl. J. Med. 386 , 1397–1408 (2022). 35172054 10.1056/NEJMoa2118542 PMC8908851

460. Marzolini C Recommendations for the Management of Drug–Drug Interactions Between the COVID‐19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications Clin. Pharmacol. Ther. 2022 112 1191 1200 10.1002/cpt.2646 35567754 PMC9348462 Marzolini, C. et al. Recommendations for the Management of Drug–Drug Interactions Between the COVID‐19 Antiviral Nirmatrelvir/Ritonavir (Paxlovid) and Comedications. Clin. Pharmacol. Ther. 112 , 1191–1200 (2022). 35567754 10.1002/cpt.2646 PMC9348462

461. Xia S Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion Cell Res. 2020 30 343 355 10.1038/s41422-020-0305-x 32231345 PMC7104723 Xia, S. et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 30 , 343–355 (2020). 32231345 10.1038/s41422-020-0305-x PMC7104723

462. Zhou J A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases Acta Pharm. Sin. B. 2022 12 1652 1661 10.1016/j.apsb.2021.07.026 34367893 PMC8327648 Zhou, J. et al. A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases. Acta Pharm. Sin. B. 12 , 1652–1661 (2022). 34367893 10.1016/j.apsb.2021.07.026 PMC8327648

463. Lan Q A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern Viruses 2022 14 549 10.3390/v14030549 35336956 PMC8955410 Lan, Q. et al. A Palmitic Acid-Conjugated, Peptide-Based pan-CoV Fusion Inhibitor Potently Inhibits Infection of SARS-CoV-2 Omicron and Other Variants of Concern. Viruses 14 , 549 (2022). 35336956 10.3390/v14030549 PMC8955410

464. Xing L A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern Viruses 2022 14 597 10.3390/v14030597 35337003 PMC8955665 Xing, L. et al. A Five-Helix-Based SARS-CoV-2 Fusion Inhibitor Targeting Heptad Repeat 2 Domain against SARS-CoV-2 and Its Variants of Concern. Viruses 14 , 597 (2022). 35337003 10.3390/v14030597 PMC8955665

465. Zhu J Following the rule: formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors Biochem. Biophys. Res. Commun. 2004 319 283 288 10.1016/j.bbrc.2004.04.141 15158473 PMC7111185 Zhu, J. et al. Following the rule: formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors. Biochem. Biophys. Res. Commun. 319 , 283–288 (2004). 15158473 10.1016/j.bbrc.2004.04.141 PMC7111185

466. Gao J Structure of the Fusion Core and Inhibition of Fusion by a Heptad Repeat Peptide Derived from the S Protein of Middle East Respiratory Syndrome Coronavirus J. Virol. 2013 87 13134 13140 10.1128/JVI.02433-13 24067982 PMC3838252 Gao, J. et al. Structure of the Fusion Core and Inhibition of Fusion by a Heptad Repeat Peptide Derived from the S Protein of Middle East Respiratory Syndrome Coronavirus. J. Virol. 87 , 13134–13140 (2013). 24067982 10.1128/JVI.02433-13 PMC3838252

467. Sun H Structural basis of HCoV-19 fusion core and an effective inhibition peptide against virus entry Emerg. Microbes Infect. 2020 9 1238 1241 10.1080/22221751.2020.1770631 32482145 PMC7448930 Sun, H. et al. Structural basis of HCoV-19 fusion core and an effective inhibition peptide against virus entry. Emerg. Microbes Infect. 9 , 1238–1241 (2020). 32482145 10.1080/22221751.2020.1770631 PMC7448930

468. Wu L A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery Sci. China Life Sci. 2023 66 2201 2213 10.1007/s11427-023-2410-5 37574525 Wu, L. et al. A pan-coronavirus peptide inhibitor prevents SARS-CoV-2 infection in mice by intranasal delivery. Sci. China Life Sci. 66 , 2201–2213 (2023). 37574525 10.1007/s11427-023-2410-5

469. Yu D Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants Emerg. Microbes Infect. 2021 10 1227 1240 10.1080/22221751.2021.1937329 34057039 PMC8216258 Yu, D. et al. Structure-based design and characterization of novel fusion-inhibitory lipopeptides against SARS-CoV-2 and emerging variants. Emerg. Microbes Infect. 10 , 1227–1240 (2021). 34057039 10.1080/22221751.2021.1937329 PMC8216258

470. Bi W An enhanced broad-spectrum peptide inhibits Omicron variants in vivo Cell Rep. Med. 2024 5 101418 10.1016/j.xcrm.2024.101418 38340726 PMC10897629 Bi, W. et al. An enhanced broad-spectrum peptide inhibits Omicron variants in vivo. Cell Rep. Med. 5 , 101418 (2024). 38340726 10.1016/j.xcrm.2024.101418 PMC10897629

471. Calès P Vapreotide acetate for the treatment of esophageal variceal bleeding Expert Rev. Gastroenterol. Hepatol. 2008 2 185 192 10.1586/17474124.2.2.185 19072353 Calès, P. Vapreotide acetate for the treatment of esophageal variceal bleeding. Expert Rev. Gastroenterol. Hepatol. 2 , 185–192 (2008). 19072353 10.1586/17474124.2.2.185

472. Fortune BE Jackson J Leonard J Trotter JF Vapreotide: a somatostatin analog for the treatment of acute variceal bleeding Expert Opin. Pharmacother. 2009 10 2337 2342 10.1517/14656560903207019 19708854 Fortune, B. E., Jackson, J., Leonard, J. & Trotter, J. F. Vapreotide: a somatostatin analog for the treatment of acute variceal bleeding. Expert Opin. Pharmacother. 10 , 2337–2342 (2009). 19708854 10.1517/14656560903207019

473. Calès P Early administration of vapreotide for variceal bleeding in patients with cirrhosis N. Engl. J. Med. 2001 344 23 28 10.1056/NEJM200101043440104 11136956 Calès, P. et al. Early administration of vapreotide for variceal bleeding in patients with cirrhosis. N. Engl. J. Med. 344 , 23–28 (2001). 11136956 10.1056/NEJM200101043440104

474. Cho SB Comparison of terlipressin and octreotide with variceal ligation for controlling acute esophageal variceal bleeding-a randomized prospective study Korean J. Hepatol. 2006 12 385 393 16998290 Cho, S. B. et al. Comparison of terlipressin and octreotide with variceal ligation for controlling acute esophageal variceal bleeding-a randomized prospective study. Korean J. Hepatol. 12 , 385–393 (2006). 16998290

475. Thangaraj SR Srinivasan M Arzoun H Thomas SS A Systematic Review of the Emerging Treatment for Hepatorenal Syndrome With a Principal Focus on Terlipressin: A Recent FDA-Approved Drug Cureus 2023 15 e42367 37621788 10.7759/cureus.42367 PMC10445509 Thangaraj, S. R., Srinivasan, M., Arzoun, H. & Thomas, S. S. A Systematic Review of the Emerging Treatment for Hepatorenal Syndrome With a Principal Focus on Terlipressin: A Recent FDA-Approved Drug. Cureus 15 , e42367 (2023). 37621788 10.7759/cureus.42367 PMC10445509

476. Holtmann GJ Ford AC Talley NJ Pathophysiology of irritable bowel syndrome Lancet Gastroenterol. Hepatol. 2016 1 133 146 10.1016/S2468-1253(16)30023-1 28404070 Holtmann, G. J., Ford, A. C. & Talley, N. J. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol. Hepatol. 1 , 133–146 (2016). 28404070 10.1016/S2468-1253(16)30023-1

477. Ford AC Sperber AD Corsetti M Camilleri M Functional gastrointestinal disorders 2 irritable bowel syndrome Lancet 2020 396 1675 1688 10.1016/S0140-6736(20)31548-8 33049223 Ford, A. C., Sperber, A. D., Corsetti, M. & Camilleri, M. Functional gastrointestinal disorders 2 irritable bowel syndrome. Lancet 396 , 1675–1688 (2020). 33049223 10.1016/S0140-6736(20)31548-8

478. Bryant AP Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract Life Sci. 2010 86 760 765 10.1016/j.lfs.2010.03.015 20307554 Bryant, A. P. et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 86 , 760–765 (2010). 20307554 10.1016/j.lfs.2010.03.015

479. Love BL Johnson A Smith LS Linaclotide: A novel agent for chronic constipation and irritable bowel syndrome Am. J. Health Syst. Pharm. 2014 71 1081 1091 10.2146/ajhp130575 24939497 Love, B. L., Johnson, A. & Smith, L. S. Linaclotide: A novel agent for chronic constipation and irritable bowel syndrome. Am. J. Health Syst. Pharm. 71 , 1081–1091 (2014). 24939497 10.2146/ajhp130575

480. Pitari GM Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis Drug Des. Devel. Ther. 2013 7 351 360 10.2147/DDDT.S32252 23637522 PMC3634396 Pitari, G. M. Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis. Drug Des. Devel. Ther. 7 , 351–360 (2013). 23637522 10.2147/DDDT.S32252 PMC3634396

481. Shailubhai K Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses Digestive Dis. Sci. 2013 58 2580 2586 10.1007/s10620-013-2684-z 23625291 Shailubhai, K. et al. Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses. Digestive Dis. Sci. 58 , 2580–2586 (2013). 10.1007/s10620-013-2684-z 23625291

482. Mayo BJ The GLP-2 analogue elsiglutide reduces diarrhoea caused by the tyrosine kinase inhibitor lapatinib in rats Cancer Chemother. Pharmacol. 2020 85 793 803 10.1007/s00280-020-04040-0 32060615 Mayo, B. J. et al. The GLP-2 analogue elsiglutide reduces diarrhoea caused by the tyrosine kinase inhibitor lapatinib in rats. Cancer Chemother. Pharmacol. 85 , 793–803 (2020). 32060615 10.1007/s00280-020-04040-0

483. Farr S Chess-Williams R McDermott C Gemcitabine enhances release of atp but not acetylcholine or pge(2) from bladder urothelial cells Asia Pac. J. Clin. Oncol. 2014 10 131 131 Farr, S., Chess-Williams, R. & McDermott, C. Gemcitabine enhances release of atp but not acetylcholine or pge(2) from bladder urothelial cells. Asia Pac. J. Clin. Oncol. 10 , 131–131 (2014).

484. Mayo B The new selective glp-2 receptor agonist, elsiglutide, improves irinotecan-induced diarrhoea and mucositis in the rat Asia Pac. J. Clin. Oncol. 2014 10 134 134 Mayo, B. et al. The new selective glp-2 receptor agonist, elsiglutide, improves irinotecan-induced diarrhoea and mucositis in the rat. Asia Pac. J. Clin. Oncol. 10 , 134–134 (2014).

485. Karthaus, M. et al. Elsiglutide in the primary prevention of chemotherapy (CT)-induced diarrhea in patients with colorectal cancer (CRC) receiving 5-fluorouracil (5-FU)-based CT: A multinational, randomized, double-blind, placebo-controlled study. J. Clin. Oncol . 35 , 10101–10101.

486. Vaz M Silvestre S Alzheimer’s disease: Recent treatment strategies Eur. J. Pharmacol. 2020 887 173554 10.1016/j.ejphar.2020.173554 32941929 Vaz, M. & Silvestre, S. Alzheimer’s disease: Recent treatment strategies. Eur. J. Pharmacol. 887 , 173554 (2020). 32941929 10.1016/j.ejphar.2020.173554

487. Walsh DM Selkoe DJ Amyloid β-protein and beyond: the path forward in Alzheimer’s disease Curr. Opin. Neurobiol. 2020 61 116 124 10.1016/j.conb.2020.02.003 32197217 Walsh, D. M. & Selkoe, D. J. Amyloid β-protein and beyond: the path forward in Alzheimer’s disease. Curr. Opin. Neurobiol. 61 , 116–124 (2020). 32197217 10.1016/j.conb.2020.02.003

488. Chidambaram H Chinnathambi S G-Protein Coupled Receptors and Tau-different Roles in Alzheimer’s Disease Neuroscience 2020 438 198 214 10.1016/j.neuroscience.2020.04.019 32335218 Chidambaram, H. & Chinnathambi, S. G-Protein Coupled Receptors and Tau-different Roles in Alzheimer’s Disease. Neuroscience 438 , 198–214 (2020). 32335218 10.1016/j.neuroscience.2020.04.019

489. Chen ZR Huang JB Yang SL Hong FF Role of Cholinergic Signaling in Alzheimer’s Disease Molecules 2022 27 1816 10.3390/molecules27061816 35335180 PMC8949236 Chen, Z. R., Huang, J. B., Yang, S. L. & Hong, F. F. Role of Cholinergic Signaling in Alzheimer’s Disease. Molecules 27 , 1816 (2022). 35335180 10.3390/molecules27061816 PMC8949236

490. Bonda DJ Oxidative stress in Alzheimer disease: a possibility for prevention Neuropharmacology 2010 59 290 294 10.1016/j.neuropharm.2010.04.005 20394761 Bonda, D. J. et al. Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59 , 290–294 (2010). 20394761 10.1016/j.neuropharm.2010.04.005

491. Huat TJ Metal Toxicity Links to Alzheimer’s Disease and Neuroinflammation J. Mol. Biol. 2019 431 1843 1868 10.1016/j.jmb.2019.01.018 30664867 PMC6475603 Huat, T. J. et al. Metal Toxicity Links to Alzheimer’s Disease and Neuroinflammation. J. Mol. Biol. 431 , 1843–1868 (2019). 30664867 10.1016/j.jmb.2019.01.018 PMC6475603

492. Selkoe DJ Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein J. Alzheimers Dis. 2001 3 75 80 10.3233/JAD-2001-3111 12214075 Selkoe, D. J. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J. Alzheimers Dis. 3 , 75–80 (2001). 12214075 10.3233/jad-2001-3111

493. Nasb M Tao W Chen N Alzheimer’s Disease Puzzle: Delving into Pathogenesis Hypotheses Aging Dis. 2024 15 43 73 37450931 10.14336/AD.2023.0608 PMC10796101 Nasb, M., Tao, W. & Chen, N. Alzheimer’s Disease Puzzle: Delving into Pathogenesis Hypotheses. Aging Dis. 15 , 43–73 (2024). 37450931 10.14336/AD.2023.0608 PMC10796101

494. Goedert M Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease Neuron 1989 3 519 526 10.1016/0896-6273(89)90210-9 2484340 Goedert, M. et al. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3 , 519–526 (1989). 2484340 10.1016/0896-6273(89)90210-9

495. Brody AH Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy Mol. Neurodegener. 2022 17 32 10.1186/s13024-022-00526-y 35501917 PMC9063299 Brody, A. H. et al. Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy. Mol. Neurodegener. 17 , 32 (2022). 35501917 10.1186/s13024-022-00526-y PMC9063299

496. Miklossy J Chronic inflammation and amyloidogenesis in Alzheimer’s disease - role of Spirochetes J. Alzheimers Dis. 2008 13 381 391 10.3233/JAD-2008-13404 18487847 Miklossy, J. Chronic inflammation and amyloidogenesis in Alzheimer’s disease - role of Spirochetes. J. Alzheimers Dis. 13 , 381–391 (2008). 18487847 10.3233/jad-2008-13404

497. Fahnestock M Shekari A ProNGF and Neurodegeneration in Alzheimer’s Disease Front. Neurosci. 2019 13 129 10.3389/fnins.2019.00129 30853882 PMC6395390 Fahnestock, M. & Shekari, A. ProNGF and Neurodegeneration in Alzheimer’s Disease. Front. Neurosci. 13 , 129 (2019). 30853882 10.3389/fnins.2019.00129 PMC6395390

498. Knopman DS Alzheimer disease Nat. Rev. Dis. Prim. 2021 7 33 10.1038/s41572-021-00269-y 33986301 PMC8574196 Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Prim. 7 , 33 (2021). 33986301 10.1038/s41572-021-00269-y PMC8574196

499. Ichimata S Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome Int. J. Mol. Sci. 2023 24 11596 10.3390/ijms241411596 37511361 PMC10380583 Ichimata, S. et al. Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome. Int. J. Mol. Sci. 24 , 11596 (2023). 37511361 10.3390/ijms241411596 PMC10380583

500. Athar T Al Balushi K Khan SA Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease Mol. Biol. Rep. 2021 48 5629 5645 10.1007/s11033-021-06512-9 34181171 PMC8236749 Athar, T., Al Balushi, K. & Khan, S. A. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol. Biol. Rep. 48 , 5629–5645 (2021). 34181171 10.1007/s11033-021-06512-9 PMC8236749

501. Ghosh AK Tang J Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer’s Disease ChemMedChem 2015 10 1463 1466 10.1002/cmdc.201500216 26140607 PMC6029879 Ghosh, A. K. & Tang, J. Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer’s Disease. ChemMedChem 10 , 1463–1466 (2015). 26140607 10.1002/cmdc.201500216 PMC6029879

502. Ghosh AK Structure-based design: Potent inhibitors of human brain memapsin 2 (β-secretase) J. Med. Chem. 2001 44 2865 2868 10.1021/jm0101803 11520194 Ghosh, A. K. et al. Structure-based design: Potent inhibitors of human brain memapsin 2 (β-secretase). J. Med. Chem. 44 , 2865–2868 (2001). 11520194 10.1021/jm0101803

503. Eketjäll S AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics J. Alzheimers Dis. 2016 50 1109 1123 10.3233/JAD-150834 26890753 PMC4927864 Eketjäll, S. et al. AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. J. Alzheimers Dis. 50 , 1109–1123 (2016). 26890753 10.3233/JAD-150834 PMC4927864

504. Xu P Screening of specific binding peptides using phage-display techniques and their biosensing applications TrAC, Trends Anal. Chem. 2021 137 116229 10.1016/j.trac.2021.116229 Xu, P. et al. Screening of specific binding peptides using phage-display techniques and their biosensing applications. TrAC, Trends Anal. Chem. 137 , 116229 (2021).

505. Orner BP Liu L Murphy RM Kiessling LL Phage display affords peptides that modulate beta-amyloid aggregation J. Am. Chem. Soc. 2006 128 11882 11889 10.1021/ja0619861 16953628 Orner, B. P., Liu, L., Murphy, R. M. & Kiessling, L. L. Phage display affords peptides that modulate beta-amyloid aggregation. J. Am. Chem. Soc. 128 , 11882–11889 (2006). 16953628 10.1021/ja0619861

506. Andreetto E A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly Angew. Chem. Int Ed. Engl. 2015 54 13095 13100 10.1002/anie.201504973 26336938 Andreetto, E. et al. A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly. Angew. Chem. Int Ed. Engl. 54 , 13095–13100 (2015). 26336938 10.1002/anie.201504973

507. Spanopoulou A Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements Angew. Chem. Int Ed. Engl. 2018 57 14503 14508 10.1002/anie.201802979 29908130 Spanopoulou, A. et al. Designed Macrocyclic Peptides as Nanomolar Amyloid Inhibitors Based on Minimal Recognition Elements. Angew. Chem. Int Ed. Engl. 57 , 14503–14508 (2018). 29908130 10.1002/anie.201802979

508. Wang C Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide Int. J. Mol. Sci. 2023 24 13110 10.3390/ijms241713110 37685916 PMC10487952 Wang, C. et al. Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide. Int. J. Mol. Sci. 24 , 13110 (2023). 37685916 10.3390/ijms241713110 PMC10487952

509. Xue C Lin TY Chang D Guo Z Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation R. Soc. Open Sci. 2017 4 160696 10.1098/rsos.160696 28280572 PMC5319338 Xue, C., Lin, T. Y., Chang, D. & Guo, Z. Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. R. Soc. Open Sci. 4 , 160696 (2017). 28280572 10.1098/rsos.160696 PMC5319338

510. Wegmann S Biernat J Mandelkow E A current view on Tau protein phosphorylation in Alzheimer’s disease Curr. Opin. Neurobiol. 2021 69 131 138 10.1016/j.conb.2021.03.003 33892381 Wegmann, S., Biernat, J. & Mandelkow, E. A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr. Opin. Neurobiol. 69 , 131–138 (2021). 33892381 10.1016/j.conb.2021.03.003

511. Zhang H Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease Int. J. Biol. Sci. 2021 17 2181 2192 10.7150/ijbs.57078 34239348 PMC8241728 Zhang, H. et al. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease. Int. J. Biol. Sci. 17 , 2181–2192 (2021). 34239348 10.7150/ijbs.57078 PMC8241728

512. Congdon EE Tau-targeting therapies for Alzheimer disease: current status and future directions Nat. Rev. Neurol. 2023 19 715 736 10.1038/s41582-023-00883-2 37875627 PMC10965012 Congdon, E. E. et al. Tau-targeting therapies for Alzheimer disease: current status and future directions. Nat. Rev. Neurol. 19 , 715–736 (2023). 37875627 10.1038/s41582-023-00883-2 PMC10965012

513. Zheng J A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies Signal Transduct. Target Ther. 2021 6 269 10.1038/s41392-021-00669-2 34262014 PMC8280143 Zheng, J. et al. A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies. Signal Transduct. Target Ther. 6 , 269 (2021). 34262014 10.1038/s41392-021-00669-2 PMC8280143

514. Leng F Edison P Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 2021 17 157 172 10.1038/s41582-020-00435-y 33318676 Leng, F. & Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat. Rev. Neurol. 17 , 157–172 (2021). 33318676 10.1038/s41582-020-00435-y

515. Rajesh Y Kanneganti TD Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease Cells 2022 11 1885 10.3390/cells11121885 35741014 PMC9221514 Rajesh, Y. & Kanneganti, T. D. Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease. Cells 11 , 1885 (2022). 35741014 10.3390/cells11121885 PMC9221514

516. Alrouji M The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer’s diseases Diabetol. Metab. Syndr. 2023 15 101 10.1186/s13098-023-01082-1 37173803 PMC10182652 Alrouji, M. et al. The potential role of human islet amyloid polypeptide in type 2 diabetes mellitus and Alzheimer’s diseases. Diabetol. Metab. Syndr. 15 , 101 (2023). 37173803 10.1186/s13098-023-01082-1 PMC10182652

517. Nguengang Wakap S Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database Eur. J. Hum. Genet. 2020 28 165 173 10.1038/s41431-019-0508-0 31527858 PMC6974615 Nguengang Wakap, S. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 28 , 165–173 (2020). 31527858 10.1038/s41431-019-0508-0 PMC6974615

518. Roessler HI Knoers N van Haelst MM van Haaften G Drug Repurposing for Rare Diseases Trends Pharmacol. Sci. 2021 42 255 267 10.1016/j.tips.2021.01.003 33563480 Roessler, H. I., Knoers, N., van Haelst, M. M. & van Haaften, G. Drug Repurposing for Rare Diseases. Trends Pharmacol. Sci. 42 , 255–267 (2021). 33563480 10.1016/j.tips.2021.01.003

519. Sardana D Drug repositioning for orphan diseases Brief. Bioinform. 2011 12 346 356 10.1093/bib/bbr021 21504985 Sardana, D. et al. Drug repositioning for orphan diseases. Brief. Bioinform. 12 , 346–356 (2011). 21504985 10.1093/bib/bbr021

520. Posey JE Genome sequencing and implications for rare disorders Orphanet J. Rare Dis. 2019 14 153 10.1186/s13023-019-1127-0 31234920 PMC6591893 Posey, J. E. Genome sequencing and implications for rare disorders. Orphanet J. Rare Dis. 14 , 153 (2019). 31234920 10.1186/s13023-019-1127-0 PMC6591893

521. Guillem P Rare diseases in disabled children: an epidemiological survey Arch. Dis. Child. 2008 93 115 118 10.1136/adc.2006.104455 17942587 Guillem, P. et al. Rare diseases in disabled children: an epidemiological survey. Arch. Dis. Child. 93 , 115–118 (2008). 17942587 10.1136/adc.2006.104455

522. Jeffrey LN Rett syndrome: Revised diagnostic criteria and nomenclature Ann. Neurol. 2010 68 944 950 10.1002/ana.22124 21154482 PMC3058521 Jeffrey, L. N. et al. Rett syndrome: Revised diagnostic criteria and nomenclature. Ann. Neurol. 68 , 944–950 (2010). 21154482 10.1002/ana.22124 PMC3058521

523. Valenti D Vacca RA Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes Int. J. Mol. Sci. 2023 24 12488 10.3390/ijms241512488 37569863 PMC10419900 Valenti, D. & Vacca, R. A. Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes. Int. J. Mol. Sci. 24 , 12488 (2023). 37569863 10.3390/ijms241512488 PMC10419900

524. Neul JL Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study Nat. Med. 2023 29 1468 1475 10.1038/s41591-023-02398-1 37291210 PMC10287558 Neul, J. L. et al. Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nat. Med. 29 , 1468–1475 (2023). 37291210 10.1038/s41591-023-02398-1 PMC10287558

525. Bickerdike MJ NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke J. Neurol. Sci. 2009 278 85 90 10.1016/j.jns.2008.12.003 19157421 Bickerdike, M. J. et al. NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke. J. Neurol. Sci. 278 , 85–90 (2009). 19157421 10.1016/j.jns.2008.12.003

526. Al Shaer D Al Musaimi O Albericio F de la Torre BG 2023 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharm. 2024 17 243 10.3390/ph17020243 PMC10893093 38399458 Al Shaer, D., Al Musaimi, O., Albericio, F. & de la Torre, B. G. 2023 FDA TIDES (Peptides and Oligonucleotides). Harvest. Pharm. 17 , 243 (2024). 10.3390/ph17020243 PMC10893093 38399458

527. Menon D Bril V Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals Drugs 2022 82 865 887 10.1007/s40265-022-01726-y 35639288 PMC9152838 Menon, D. & Bril, V. Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals. Drugs 82 , 865–887 (2022). 35639288 10.1007/s40265-022-01726-y PMC9152838

528. Gilhus NE Verschuuren JJ Myasthenia gravis: subgroup classification and therapeutic strategies Lancet Neurol. 2015 14 1023 1036 10.1016/S1474-4422(15)00145-3 26376969 Gilhus, N. E. & Verschuuren, J. J. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 14 , 1023–1036 (2015). 26376969 10.1016/S1474-4422(15)00145-3

529. Krisinger MJ Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway Blood 2012 120 1717 1725 10.1182/blood-2012-02-412080 22802338 Krisinger, M. J. et al. Thrombin generates previously unidentified C5 products that support the terminal complement activation pathway. Blood 120 , 1717–1725 (2012). 22802338 10.1182/blood-2012-02-412080

530. Foley JH Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin EBioMedicine 2016 5 175 182 10.1016/j.ebiom.2016.02.011 27077125 PMC4816834 Foley, J. H. et al. Complement Activation in Arterial and Venous Thrombosis is Mediated by Plasmin. EBioMedicine 5 , 175–182 (2016). 27077125 10.1016/j.ebiom.2016.02.011 PMC4816834

531. Pironi L Definitions of intestinal failure and the short bowel syndrome Best. Pract. Res. Clin. Gastroenterol. 2016 30 173 185 10.1016/j.bpg.2016.02.011 27086884 Pironi, L. Definitions of intestinal failure and the short bowel syndrome. Best. Pract. Res. Clin. Gastroenterol. 30 , 173–185 (2016). 27086884 10.1016/j.bpg.2016.02.011

532. Massironi S Understanding short bowel syndrome: Current status and future perspectives Dig. Liver Dis. 2020 52 253 261 10.1016/j.dld.2019.11.013 31892505 Massironi, S. et al. Understanding short bowel syndrome: Current status and future perspectives. Dig. Liver Dis. 52 , 253–261 (2020). 31892505 10.1016/j.dld.2019.11.013

533. Diamanti A Etiology and Management of Pediatric Intestinal Failure: Focus on the Non-Digestive Causes Nutrients 2021 13 786 10.3390/nu13030786 33673586 PMC7997222 Diamanti, A. et al. Etiology and Management of Pediatric Intestinal Failure: Focus on the Non-Digestive Causes. Nutrients 13 , 786 (2021). 33673586 10.3390/nu13030786 PMC7997222

534. Jeppesen PB Fuglsang KA Nutritional Therapy in Adult Short Bowel Syndrome Patients with Chronic Intestinal Failure Gastroenterol. Clin. North Am. 2018 47 61 75 10.1016/j.gtc.2017.10.004 29413019 Jeppesen, P. B. & Fuglsang, K. A. Nutritional Therapy in Adult Short Bowel Syndrome Patients with Chronic Intestinal Failure. Gastroenterol. Clin. North Am. 47 , 61–75 (2018). 29413019 10.1016/j.gtc.2017.10.004

535. Nightingale J Guidelines for management of patients with a short bowel Gut 2006 55 iv1 iv12 10.1136/gut.2006.091108 16837533 PMC2806687 Nightingale, J. Guidelines for management of patients with a short bowel. Gut 55 , iv1–iv12 (2006). 16837533 10.1136/gut.2006.091108 PMC2806687

536. Lee J Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport Mol. Metab. 2017 6 245 255 10.1016/j.molmet.2017.01.005 28271031 PMC5324020 Lee, J. et al. Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport. Mol. Metab. 6 , 245–255 (2017). 28271031 10.1016/j.molmet.2017.01.005 PMC5324020

537. Kim ES Keam SJ Teduglutide: A Review in Short Bowel Syndrome Drugs 2017 77 345 352 10.1007/s40265-017-0703-7 28194723 Kim, E. S. & Keam, S. J. Teduglutide: A Review in Short Bowel Syndrome. Drugs 77 , 345–352 (2017). 28194723 10.1007/s40265-017-0703-7

538. Jeppesen PB Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure Gastroenterology 2012 143 1473 1481 10.1053/j.gastro.2012.09.007 22982184 Jeppesen, P. B. et al. Teduglutide Reduces Need for Parenteral Support Among Patients With Short Bowel Syndrome With Intestinal Failure. Gastroenterology 143 , 1473–1481 (2012). 22982184 10.1053/j.gastro.2012.09.007

539. Zhang T Long-term outcomes of various pediatric short bowel syndrome in China Pediatr. Surg. Int. 2021 37 495 502 10.1007/s00383-020-04797-8 33394086 Zhang, T. et al. Long-term outcomes of various pediatric short bowel syndrome in China. Pediatr. Surg. Int. 37 , 495–502 (2021). 33394086 10.1007/s00383-020-04797-8

540. Jeppesen PB The non-surgical treatment of adult patients with short bowel syndrome Expert Opin. Orphan Drugs 2013 7 527 538 10.1517/21678707.2013.814536 Jeppesen, P. B. The non-surgical treatment of adult patients with short bowel syndrome. Expert Opin. Orphan Drugs 7 , 527–538 (2013).

541. Jeppesen PB Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients Gut 2005 54 1224 1231 10.1136/gut.2004.061440 16099790 PMC1774653 Jeppesen, P. B. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients. Gut 54 , 1224–1231 (2005). 16099790 10.1136/gut.2004.061440 PMC1774653

542. Blair HA Etelcalcetide: First Global Approval Drugs 2016 76 1787 1792 10.1007/s40265-016-0671-3 27900648 Blair, H. A. Etelcalcetide: First Global Approval. Drugs 76 , 1787–1792 (2016). 27900648 10.1007/s40265-016-0671-3

543. Hadidi N Pazuki G Preparation, characterization and in-vivo efficacy study of glatiramer acetate (GA)-hydrogel-microparticles as novel drug delivery system for GA in RRMS Sci. Rep. 2022 12 22042 10.1038/s41598-022-26640-x 36543898 PMC9772231 Hadidi, N. & Pazuki, G. Preparation, characterization and in-vivo efficacy study of glatiramer acetate (GA)-hydrogel-microparticles as novel drug delivery system for GA in RRMS. Sci. Rep. 12 , 22042 (2022). 36543898 10.1038/s41598-022-26640-x PMC9772231

544. Bell C Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis J. Pharm. Pract. 2017 31 481 488 10.1177/0897190017725984 28847230 PMC6144347 Bell, C. et al. Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis. J. Pharm. Pract. 31 , 481–488 (2017). 28847230 10.1177/0897190017725984 PMC6144347

545. Ben-Zeev B Aharoni R Nissenkorn A Arnon R Glatiramer acetate (GA, Copolymer-1) an hypothetical treatment option for Rett syndrome Med. Hypotheses 2011 76 190 193 10.1016/j.mehy.2010.09.015 20951500 Ben-Zeev, B., Aharoni, R., Nissenkorn, A. & Arnon, R. Glatiramer acetate (GA, Copolymer-1) an hypothetical treatment option for Rett syndrome. Med. Hypotheses 76 , 190–193 (2011). 20951500 10.1016/j.mehy.2010.09.015

546. Hillmen P Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria N. Engl. J. Med. 2021 384 1028 1037 10.1056/NEJMoa2029073 33730455 Hillmen, P. et al. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N. Engl. J. Med. 384 , 1028–1037 (2021). 33730455 10.1056/NEJMoa2029073

547. Jiang M Identification of osteogenic progenitor cell-targeted peptides that augment bone formation Nat. Commun. 2020 11 4278 10.1038/s41467-020-17417-9 32855388 PMC7453024 Jiang, M. et al. Identification of osteogenic progenitor cell-targeted peptides that augment bone formation. Nat. Commun. 11 , 4278 (2020). 32855388 10.1038/s41467-020-17417-9 PMC7453024

548. McClung MR Romosozumab in Postmenopausal Women with Low Bone Mineral Density N. Engl. J. Med. 2014 370 412 420 10.1056/NEJMoa1305224 24382002 McClung, M. R. et al. Romosozumab in Postmenopausal Women with Low Bone Mineral Density. N. Engl. J. Med. 370 , 412–420 (2014). 24382002 10.1056/NEJMoa1305224

549. Cosman F Romosozumab Treatment in Postmenopausal Women with Osteoporosis N. Engl. J. Med. 2016 375 1532 1543 10.1056/NEJMoa1607948 27641143 Cosman, F. et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 375 , 1532–1543 (2016). 27641143 10.1056/NEJMoa1607948

550. Genant HK Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass J. Bone Miner. Res. 2017 32 181 187 10.1002/jbmr.2932 27487526 Genant, H. K. et al. Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass. J. Bone Miner. Res. 32 , 181–187 (2017). 27487526 10.1002/jbmr.2932

551. Padhi D Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: A randomized, double-blind, placebo-controlled study J. Clin. Pharmacol. 2014 54 168 178 10.1002/jcph.239 24272917 Padhi, D. et al. Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: A randomized, double-blind, placebo-controlled study. J. Clin. Pharmacol. 54 , 168–178 (2014). 24272917 10.1002/jcph.239

552. Pigossi S Role of Osteogenic Growth Peptide (OGP) and OGP(10–14) in Bone Regeneration: A Review Int. J. Mol. Sci. 2016 17 1885 10.3390/ijms17111885 27879684 PMC5133884 Pigossi, S. et al. Role of Osteogenic Growth Peptide (OGP) and OGP(10–14) in Bone Regeneration: A Review. Int. J. Mol. Sci. 17 , 1885 (2016). 27879684 10.3390/ijms17111885 PMC5133884

553. Ashina M Migraine: disease characterisation, biomarkers, and precision medicine Lancet 2021 397 1496 1504 10.1016/S0140-6736(20)32162-0 33773610 Ashina, M. et al. Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 397 , 1496–1504 (2021). 33773610 10.1016/S0140-6736(20)32162-0

554. Russo AF Calcitonin gene-related peptide (CGRP): a new target for migraine Annu Rev. Pharm. Toxicol. 2015 55 533 552 10.1146/annurev-pharmtox-010814-124701 PMC4392770 25340934 Russo, A. F. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev. Pharm. Toxicol. 55 , 533–552 (2015). 10.1146/annurev-pharmtox-010814-124701 PMC4392770 25340934

555. Yuan H Lauritsen CG Kaiser EA Silberstein SD CGRP Monoclonal Antibodies for Migraine: Rationale and Progress Biodrugs 2017 31 487 501 10.1007/s40259-017-0250-5 29116598 Yuan, H., Lauritsen, C. G., Kaiser, E. A. & Silberstein, S. D. CGRP Monoclonal Antibodies for Migraine: Rationale and Progress. Biodrugs 31 , 487–501 (2017). 29116598 10.1007/s40259-017-0250-5

556. Chan KY Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries J. Pharm. Exp. Ther. 2010 334 746 752 10.1124/jpet.110.165993 20573757 Chan, K. Y. et al. Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J. Pharm. Exp. Ther. 334 , 746–752 (2010). 10.1124/jpet.110.165993 20573757

557. de Vries T Villalón CM MaassenVanDenBrink A Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans Pharm. Ther. 2020 211 107528 10.1016/j.pharmthera.2020.107528 32173558 de Vries, T., Villalón, C. M. & MaassenVanDenBrink, A. Pharmacological treatment of migraine: CGRP and 5-HT beyond the triptans. Pharm. Ther. 211 , 107528 (2020). 10.1016/j.pharmthera.2020.107528 32173558

558. Lionetto L Calcitonin gene-related peptide (CGRP) receptor antagonist Treat. migraine 2019 44 635 Lionetto, L. et al. Calcitonin gene-related peptide (CGRP) receptor antagonist. Treat. migraine 44 , 635 (2019).

559. Marcus R BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial Cephalalgia 2014 34 114 125 10.1177/0333102413500727 23965396 Marcus, R. et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34 , 114–125 (2014). 23965396 10.1177/0333102413500727

560. Croop R Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial Lancet 2019 394 737 745 10.1016/S0140-6736(19)31606-X 31311674 Croop, R. et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet 394 , 737–745 (2019). 31311674 10.1016/S0140-6736(19)31606-X

561. Boinpally R Shebley M Trugman JM Atogepant: Mechanism of action, clinical and translational science Clin. Transl. Sci. 2024 17 e13707 10.1111/cts.13707 38266063 PMC10777605 Boinpally, R., Shebley, M. & Trugman, J. M. Atogepant: Mechanism of action, clinical and translational science. Clin. Transl. Sci. 17 , e13707 (2024). 38266063 10.1111/cts.13707 PMC10777605

562. Ailani J Atogepant for the Preventive Treatment of Migraine N. Engl. J. Med 2021 385 695 706 10.1056/NEJMoa2035908 34407343 Ailani, J. et al. Atogepant for the Preventive Treatment of Migraine. N. Engl. J. Med 385 , 695–706 (2021). 34407343 10.1056/NEJMoa2035908

563. Luo G Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine J. Med. Chem. 2012 55 10644 10651 10.1021/jm3013147 23153230 Luo, G. et al. Discovery of (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. J. Med. Chem. 55 , 10644–10651 (2012). 23153230 10.1021/jm3013147

564. Pan KS Siow A Hay DL Walker CS Antagonism of CGRP Signaling by Rimegepant at Two Receptors Front. Pharmacol. 2020 11 1240 10.3389/fphar.2020.01240 32973499 PMC7468408 Pan, K. S., Siow, A., Hay, D. L. & Walker, C. S. Antagonism of CGRP Signaling by Rimegepant at Two Receptors. Front. Pharmacol. 11 , 1240 (2020). 32973499 10.3389/fphar.2020.01240 PMC7468408

565. Hage La Cour S Characterization of erenumab and rimegepant on calcitonin gene-related peptide induced responses in Xenopus Laevis oocytes expressing the calcitonin gene-related peptide receptor and the amylin-1 receptor J. Headache Pain. 2022 23 59 10.1186/s10194-022-01425-9 35614383 PMC9134599 Hage La Cour, S. et al. Characterization of erenumab and rimegepant on calcitonin gene-related peptide induced responses in Xenopus Laevis oocytes expressing the calcitonin gene-related peptide receptor and the amylin-1 receptor. J. Headache Pain. 23 , 59 (2022). 35614383 10.1186/s10194-022-01425-9 PMC9134599

566. Johnston K Monthly migraine days, tablet utilization, and quality of life associated with Rimegepant - post hoc results from an open label safety study (BHV3000-201) J. Headache Pain. 2022 23 10 10.1186/s10194-021-01378-5 35038983 PMC8903552 Johnston, K. et al. Monthly migraine days, tablet utilization, and quality of life associated with Rimegepant - post hoc results from an open label safety study (BHV3000-201). J. Headache Pain. 23 , 10 (2022). 35038983 10.1186/s10194-021-01378-5 PMC8903552

567. Lipton RB Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial Lancet Neurol. 2023 22 209 217 10.1016/S1474-4422(22)00517-8 36804093 Lipton, R. B. et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 22 , 209–217 (2023). 36804093 10.1016/S1474-4422(22)00517-8

568. Clem AS Fundamentals of vaccine immunology J. Glob. Infect. Dis. 2011 3 73 10.4103/0974-777X.77299 21572612 PMC3068582 Clem, A. S. Fundamentals of vaccine immunology. J. Glob. Infect. Dis. 3 , 73 (2011). 21572612 10.4103/0974-777X.77299 PMC3068582

569. Casey G Vaccines-how and why they work Nurs. N.Z. 2016 22 20 27039576 Casey, G. Vaccines-how and why they work. Nurs. N.Z. 22 , 20 (2016). 27039576

570. Stanfield BA Kousoulas KG Fernandez A Gershburg E Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses Viruses 2021 13 1637 10.3390/v13081637 34452501 PMC8402837 Stanfield, B. A., Kousoulas, K. G., Fernandez, A. & Gershburg, E. Rational Design of Live-Attenuated Vaccines against Herpes Simplex Viruses. Viruses 13 , 1637 (2021). 34452501 10.3390/v13081637 PMC8402837

571. Skwarczynski M Progress in the development of subunit vaccines against malaria Vaccines 2020 8 373 10.3390/vaccines8030373 32664421 PMC7563759 Skwarczynski, M. et al. Progress in the development of subunit vaccines against malaria. Vaccines 8 , 373 (2020). 32664421 10.3390/vaccines8030373 PMC7563759

572. Cheng JY Margo CE Ocular adverse events following vaccination: overview and update Surv. Ophthalmol. 2022 67 293 306 10.1016/j.survophthal.2021.04.001 33865883 Cheng, J. Y. & Margo, C. E. Ocular adverse events following vaccination: overview and update. Surv. Ophthalmol. 67 , 293–306 (2022). 33865883 10.1016/j.survophthal.2021.04.001

573. Koff WC Accelerating Next-Generation Vaccine Development for Global Disease Prevention Science 2013 340 1232910 10.1126/science.1232910 23723240 PMC4026248 Koff, W. C. et al. Accelerating Next-Generation Vaccine Development for Global Disease Prevention. Science 340 , 1232910 (2013). 23723240 10.1126/science.1232910 PMC4026248

574. Nakayama T Causal relationship between immunological responses and adverse reactions following vaccination Vaccine 2019 37 366 371 10.1016/j.vaccine.2018.11.045 30503656 Nakayama, T. Causal relationship between immunological responses and adverse reactions following vaccination. Vaccine 37 , 366–371 (2019). 30503656 10.1016/j.vaccine.2018.11.045

575. Zhang Y Advancedoral vaccine delivery strategies for improving the immunity Adv. Drug Del. Rev. 2021 177 113928 10.1016/j.addr.2021.113928 34411689 Zhang, Y. et al. Advancedoral vaccine delivery strategies for improving the immunity. Adv. Drug Del. Rev. 177 , 113928 (2021). 10.1016/j.addr.2021.113928 34411689

576. Malonis RJ Lai JR Vergnolle O Peptide-based vaccines: current progress and future challenges Chem. Rev. 2019 120 3210 3229 10.1021/acs.chemrev.9b00472 31804810 PMC7094793 Malonis, R. J., Lai, J. R. & Vergnolle, O. Peptide-based vaccines: current progress and future challenges. Chem. Rev. 120 , 3210–3229 (2019). 31804810 10.1021/acs.chemrev.9b00472 PMC7094793

577. Azmi F Ahmad Fuaad AAH Skwarczynski M Toth I Recent progress in adjuvant discovery for peptide-based subunit vaccines Hum. Vaccin. Immunother. 2014 10 778 796 10.4161/hv.27332 24300669 PMC4130256 Azmi, F., Ahmad Fuaad, A. A. H., Skwarczynski, M. & Toth, I. Recent progress in adjuvant discovery for peptide-based subunit vaccines. Hum. Vaccin. Immunother. 10 , 778–796 (2014). 24300669 10.4161/hv.27332 PMC4130256

578. Lee D Harnessing innate immunity using biomaterials for cancer immunotherapy Adv. Mater. 2021 33 2007576 10.1002/adma.202007576 34050699 Lee, D. et al. Harnessing innate immunity using biomaterials for cancer immunotherapy. Adv. Mater. 33 , 2007576 (2021). 10.1002/adma.202007576 34050699

579. Bellini C Horvati K Recent advances in the development of protein-and peptide-based subunit vaccines against tuberculosis Cells 2020 9 2673 10.3390/cells9122673 33333744 PMC7765234 Bellini, C. & Horvati, K. Recent advances in the development of protein-and peptide-based subunit vaccines against tuberculosis. Cells 9 , 2673 (2020). 33333744 10.3390/cells9122673 PMC7765234

580. Liu T-Y Hussein MW Toth I Skwarczynski M Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines Curr. Top. Med. Chem. 2012 12 1581 1592 10.2174/156802612802652402 22827526 Liu, T.-Y., Hussein, M. W., Toth, I. & Skwarczynski, M. Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines. Curr. Top. Med. Chem. 12 , 1581–1592 (2012). 22827526 10.2174/156802612802652402

581. Moyle PM Toth I Modern Subunit Vaccines: Development, Components, and Research Opportunities ChemMedChem 2013 8 360 376 10.1002/cmdc.201200487 23316023 Moyle, P. M. & Toth, I. Modern Subunit Vaccines: Development, Components, and Research Opportunities. ChemMedChem 8 , 360–376 (2013). 23316023 10.1002/cmdc.201200487

582. Purcell AW McCluskey J Rossjohn J More than one reason to rethink the use of peptides in vaccine design Nat. Rev. Drug Discov. 2007 6 404 414 10.1038/nrd2224 17473845 Purcell, A. W., McCluskey, J. & Rossjohn, J. More than one reason to rethink the use of peptides in vaccine design. Nat. Rev. Drug Discov. 6 , 404–414 (2007). 17473845 10.1038/nrd2224

583. Skwarczynski M Toth I Peptide-based synthetic vaccines Chem. Sci. 2016 7 842 854 10.1039/C5SC03892H 28791117 PMC5529997 Skwarczynski, M. & Toth, I. Peptide-based synthetic vaccines. Chem. Sci. 7 , 842–854 (2016). 28791117 10.1039/c5sc03892h PMC5529997

584. Ott PA An immunogenic personal neoantigen vaccine for patients with melanoma Nature 2017 547 217 221 10.1038/nature22991 28678778 PMC5577644 Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547 , 217–221 (2017). 28678778 10.1038/nature22991 PMC5577644

585. Mellman I Coukos G Dranoff G Cancer immunotherapy comes of age Nature 2011 480 480 489 10.1038/nature10673 22193102 PMC3967235 Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480 , 480–489 (2011). 22193102 10.1038/nature10673 PMC3967235

586. Song Q Zhang C-d Wu X-h Therapeutic cancer vaccines: From initial findings to prospects Immunol. Lett. 2018 196 11 21 10.1016/j.imlet.2018.01.011 29407608 Song, Q., Zhang, C.-d & Wu, X.-h Therapeutic cancer vaccines: From initial findings to prospects. Immunol. Lett. 196 , 11–21 (2018). 29407608 10.1016/j.imlet.2018.01.011

587. Cheever MA Higano CS PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA-Approved Therapeutic Cancer Vaccine Clin. Cancer Res. 2011 17 3520 3526 10.1158/1078-0432.CCR-10-3126 21471425 Cheever, M. A. & Higano, C. S. PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA-Approved Therapeutic Cancer Vaccine. Clin. Cancer Res. 17 , 3520–3526 (2011). 21471425 10.1158/1078-0432.CCR-10-3126

588. Xiao M Emerging biomaterials for tumor immunotherapy Biomater. Res. 2023 27 1 52 10.1186/s40824-023-00369-8 37194085 PMC10189985 Xiao, M. et al. Emerging biomaterials for tumor immunotherapy. Biomater. Res. 27 , 1–52 (2023). 37194085 10.1186/s40824-023-00369-8 PMC10189985

589. Mukherji B Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells Proc. Natl Acad. Sci. 1995 92 8078 8082 10.1073/pnas.92.17.8078 7644541 PMC41290 Mukherji, B. et al. Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells. Proc. Natl Acad. Sci. 92 , 8078–8082 (1995). 7644541 10.1073/pnas.92.17.8078 PMC41290

590. Belousov PV The Autoantibodies against Tumor-Associated Antigens as Potential Blood-Based Biomarkers in Thyroid Neoplasia: Rationales, Opportunities and Challenges Biomedicines 2022 10 468 10.3390/biomedicines10020468 35203677 PMC8962333 Belousov, P. V. The Autoantibodies against Tumor-Associated Antigens as Potential Blood-Based Biomarkers in Thyroid Neoplasia: Rationales, Opportunities and Challenges. Biomedicines 10 , 468 (2022). 35203677 10.3390/biomedicines10020468 PMC8962333

591. Langan D 97 High throughput screening of HPV-antigen peptides and expansion of tumor-specific T cells for adoptive cell therapy of HPV-associated malignancies J. Immunother. Cancer 2021 9 A106 A106 Langan, D. et al. 97 High throughput screening of HPV-antigen peptides and expansion of tumor-specific T cells for adoptive cell therapy of HPV-associated malignancies. J. Immunother. Cancer 9 , A106–A106 (2021).

592. Massarelli E Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16–Related Cancer: A Phase 2 Clinical Trial JAMA Oncol. 2019 5 67 73 10.1001/jamaoncol.2018.4051 30267032 PMC6439768 Massarelli, E. et al. Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16–Related Cancer: A Phase 2 Clinical Trial. JAMA Oncol. 5 , 67–73 (2019). 30267032 10.1001/jamaoncol.2018.4051 PMC6439768

593. Turajlic S Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis Lancet Oncol. 2017 18 1009 1021 10.1016/S1470-2045(17)30516-8 28694034 Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18 , 1009–1021 (2017). 28694034 10.1016/S1470-2045(17)30516-8

594. Chabeda A Therapeutic vaccines for high-risk HPV-associated diseases Papillomavirus Res. 2018 5 46 58 10.1016/j.pvr.2017.12.006 29277575 PMC5887015 Chabeda, A. et al. Therapeutic vaccines for high-risk HPV-associated diseases. Papillomavirus Res. 5 , 46–58 (2018). 29277575 10.1016/j.pvr.2017.12.006 PMC5887015

595. Zhang R Dong L Yu J Concomitant Pathogenic Mutations and Fusions of Driver Oncogenes in Tumors Front. Oncol. 2021 10 544579 10.3389/fonc.2020.544579 33520689 PMC7844084 Zhang, R., Dong, L. & Yu, J. Concomitant Pathogenic Mutations and Fusions of Driver Oncogenes in Tumors. Front. Oncol. 10 , 544579 (2021). 33520689 10.3389/fonc.2020.544579 PMC7844084

596. Nagasaka M KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond Cancer Treat. Rev. 2021 101 102309 10.1016/j.ctrv.2021.102309 34715449 Nagasaka, M. et al. KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond. Cancer Treat. Rev. 101 , 102309 (2021). 34715449 10.1016/j.ctrv.2021.102309

597. Rebuzzi SE Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer Int. J. Mol. Sci. 2021 22 2625 10.3390/ijms22052625 33807876 PMC7961376 Rebuzzi, S. E. et al. Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 22 , 2625 (2021). 33807876 10.3390/ijms22052625 PMC7961376

598. Hu Z Ott PA Wu CJ Towards personalized, tumour-specific, therapeutic vaccines for cancer Nat. Rev. Immunol. 2018 18 168 182 10.1038/nri.2017.131 29226910 PMC6508552 Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18 , 168–182 (2018). 29226910 10.1038/nri.2017.131 PMC6508552

599. Malaker SA Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia Cancer Immunol. Res. 2017 5 376 384 10.1158/2326-6066.CIR-16-0280 28314751 PMC5508727 Malaker, S. A. et al. Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia. Cancer Immunol. Res. 5 , 376–384 (2017). 28314751 10.1158/2326-6066.CIR-16-0280 PMC5508727

600. Engelhard VH MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma J. Immunother. Cancer 2020 8 e00026 10.1136/jitc-2019-000262 PMC7228659 32385144 Engelhard, V. H. et al. MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma. J. Immunother. Cancer 8 , e00026 (2020). 10.1136/jitc-2019-000262 PMC7228659 32385144

601. Schumacher TN Scheper W Kvistborg P Cancer Neoantigens Annu. Rev. Immunol. 2018 37 173 200 10.1146/annurev-immunol-042617-053402 30550719 Schumacher, T. N., Scheper, W. & Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 37 , 173–200 (2018). 30550719 10.1146/annurev-immunol-042617-053402

602. Raoufi E Epitope Prediction by Novel Immunoinformatics Approach: A State-of-the-art Review Int. J. Pept. Res. Ther. 2020 26 1155 1163 10.1007/s10989-019-09918-z 32435171 PMC7224030 Raoufi, E. et al. Epitope Prediction by Novel Immunoinformatics Approach: A State-of-the-art Review. Int. J. Pept. Res. Ther. 26 , 1155–1163 (2020). 32435171 10.1007/s10989-019-09918-z PMC7224030

603. Wells DK Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction Cell 2020 183 818 834 10.1016/j.cell.2020.09.015 33038342 PMC7652061 Wells, D. K. et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 183 , 818–834 (2020). 33038342 10.1016/j.cell.2020.09.015 PMC7652061

604. Schenck RO NeoPredPipe: high-throughput neoantigen prediction and recognition potential pipeline BMC Bioinforma. 2019 20 264 10.1186/s12859-019-2876-4 PMC6532147 31117948 Schenck, R. O. et al. NeoPredPipe: high-throughput neoantigen prediction and recognition potential pipeline. BMC Bioinforma. 20 , 264 (2019). 10.1186/s12859-019-2876-4 PMC6532147 31117948

605. Yadav M Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing Nature 2014 515 572 576 10.1038/nature14001 25428506 Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515 , 572–576 (2014). 25428506 10.1038/nature14001

606. Jensen SM Increased Frequency of Suppressive Regulatory T Cells and T Cell-Mediated Antigen Loss Results in Murine Melanoma Recurrence J. Immunol. 2012 189 767 776 10.4049/jimmunol.1103822 22723522 PMC3552612 Jensen, S. M. et al. Increased Frequency of Suppressive Regulatory T Cells and T Cell-Mediated Antigen Loss Results in Murine Melanoma Recurrence. J. Immunol. 189 , 767–776 (2012). 22723522 10.4049/jimmunol.1103822 PMC3552612

607. Zelba H Case Report: Targeting of individual somatic tumor mutations by multipeptide vaccination tailored for HLA class I and II presentation induces strong CD4 and CD8 T-cell responses in a patient with metastatic castration sensitive prostate cancer Front. Immunol. 2023 14 1271449 10.3389/fimmu.2023.1271449 37920460 PMC10619716 Zelba, H. et al. Case Report: Targeting of individual somatic tumor mutations by multipeptide vaccination tailored for HLA class I and II presentation induces strong CD4 and CD8 T-cell responses in a patient with metastatic castration sensitive prostate cancer. Front. Immunol. 14 , 1271449 (2023). 37920460 10.3389/fimmu.2023.1271449 PMC10619716

608. Marquez-Manriquez JP Multipeptide vaccine to prevent epithelial ovarian cancer relapse by microenvironment immunomodulation J. Clin. Oncol. 2020 38 e15268 e15268 10.1200/JCO.2020.38.15_suppl.e15268 Marquez-Manriquez, J. P. et al. Multipeptide vaccine to prevent epithelial ovarian cancer relapse by microenvironment immunomodulation. J. Clin. Oncol. 38 , e15268–e15268 (2020).

609. Lee KL Schlom J Hamilton DH Combination therapies utilizing neoepitope-targeted vaccines Cancer Immunol. Immunother. 2021 70 875 885 10.1007/s00262-020-02729-y 33033852 PMC7979579 Lee, K. L., Schlom, J. & Hamilton, D. H. Combination therapies utilizing neoepitope-targeted vaccines. Cancer Immunol. Immunother. 70 , 875–885 (2021). 33033852 10.1007/s00262-020-02729-y PMC7979579

610. Verdegaal EME Neoantigen landscape dynamics during human melanoma–T cell interactions Nature 2016 536 91 95 10.1038/nature18945 27350335 Verdegaal, E. M. E. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536 , 91–95 (2016). 27350335 10.1038/nature18945

611. Wang Z Peptide vaccine-conjugated mesoporous carriers synergize with immunogenic cell death and PD-L1 blockade for amplified immunotherapy of metastatic spinal J. Nanobiotechnol. 2021 19 1 16 10.1186/s12951-021-00975-5 PMC8362242 34384429 Wang, Z. et al. Peptide vaccine-conjugated mesoporous carriers synergize with immunogenic cell death and PD-L1 blockade for amplified immunotherapy of metastatic spinal. J. Nanobiotechnol. 19 , 1–16 (2021). 10.1186/s12951-021-00975-5 PMC8362242 34384429

612. Rosenberg SA Yang JC Restifo NP Cancer immunotherapy: moving beyond current vaccines Nat. Med. 2004 10 909 915 10.1038/nm1100 15340416 PMC1435696 Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10 , 909–915 (2004). 15340416 10.1038/nm1100 PMC1435696

613. Li Y Chen X CpG 1018 Is an Effective Adjuvant for Influenza Nucleoprotein Vaccines 2023 11 649 10.3390/vaccines11030649 36992232 PMC10055716 Li, Y. & Chen, X. CpG 1018 Is an Effective Adjuvant for Influenza Nucleoprotein. Vaccines 11 , 649 (2023). 36992232 10.3390/vaccines11030649 PMC10055716

614. Beck Z Immune response to antigen adsorbed to aluminum hydroxide particles: Effects of co-adsorption of ALF or ALFQ adjuvant to the aluminum-antigen complex J. Control. Release 2018 275 12 19 10.1016/j.jconrel.2018.02.006 29432824 PMC5878139 Beck, Z. et al. Immune response to antigen adsorbed to aluminum hydroxide particles: Effects of co-adsorption of ALF or ALFQ adjuvant to the aluminum-antigen complex. J. Control. Release 275 , 12–19 (2018). 29432824 10.1016/j.jconrel.2018.02.006 PMC5878139

615. Ko E-J Kang S-M Immunology and efficacy of MF59-adjuvanted vaccines Hum. Vaccin. Immunother. 2018 14 3041 3045 10.1080/21645515.2018.1495301 30015572 PMC6343625 Ko, E.-J. & Kang, S.-M. Immunology and efficacy of MF59-adjuvanted vaccines. Hum. Vaccin. Immunother. 14 , 3041–3045 (2018). 30015572 10.1080/21645515.2018.1495301 PMC6343625

616. Zhu L Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii ACS Appl. Mater. Interfaces 2021 13 40415 40428 10.1021/acsami.1c12366 34470103 Zhu, L. et al. Yeast Shells Encapsulating Adjuvant AS04 as an Antigen Delivery System for a Novel Vaccine against Toxoplasma Gondii. ACS Appl. Mater. Interfaces 13 , 40415–40428 (2021). 34470103 10.1021/acsami.1c12366

617. Yan H Nano-adjuvants and immune agonists promote antitumor immunity of peptide amphiphiles Acta Biomater. 2023 161 213 225 10.1016/j.actbio.2023.02.034 36858163 Yan, H. et al. Nano-adjuvants and immune agonists promote antitumor immunity of peptide amphiphiles. Acta Biomater. 161 , 213–225 (2023). 36858163 10.1016/j.actbio.2023.02.034

618. Gupta N Receptor-ligand based molecular interaction to discover adjuvant for immune cell TLRs to develop next-generation vaccine Int. J. Biol. Macromol. 2020 152 535 545 10.1016/j.ijbiomac.2020.02.297 32112848 Gupta, N. et al. Receptor-ligand based molecular interaction to discover adjuvant for immune cell TLRs to develop next-generation vaccine. Int. J. Biol. Macromol. 152 , 535–545 (2020). 32112848 10.1016/j.ijbiomac.2020.02.297

619. Jaroszewicz W Phage display and other peptide display technologies FEMS Microbiol. Rev. 2022 46 fuab052 10.1093/femsre/fuab052 34673942 Jaroszewicz, W. et al. Phage display and other peptide display technologies. FEMS Microbiol. Rev. 46 , fuab052 (2022). 34673942 10.1093/femsre/fuab052

620. Saw PE Song E-W Phage display screening of therapeutic peptide for cancer targeting and therapy Protein cell 2019 10 787 807 10.1007/s13238-019-0639-7 31140150 PMC6834755 Saw, P. E. & Song, E.-W. Phage display screening of therapeutic peptide for cancer targeting and therapy. Protein cell 10 , 787–807 (2019). 31140150 10.1007/s13238-019-0639-7 PMC6834755

621. Smith GP Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface Science 1985 228 1315 1317 10.1126/science.4001944 4001944 Smith, G. P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228 , 1315–1317 (1985). 4001944 10.1126/science.4001944

622. Zhang K Tang Y Chen Q Liu Y The screening of therapeutic peptides for anti-inflammation through phage display technology Int. J. Mol. Sci. 2022 23 8554 10.3390/ijms23158554 35955688 PMC9368796 Zhang, K., Tang, Y., Chen, Q. & Liu, Y. The screening of therapeutic peptides for anti-inflammation through phage display technology. Int. J. Mol. Sci. 23 , 8554 (2022). 35955688 10.3390/ijms23158554 PMC9368796

623. Zambrano-Mila MS Blacio KES Vispo NS Peptide phage display: Molecular principles and biomedical applications Ther. Innov. Regul. Sci. 2020 54 308 317 10.1007/s43441-019-00059-5 32072579 PMC7222141 Zambrano-Mila, M. S., Blacio, K. E. S. & Vispo, N. S. Peptide phage display: Molecular principles and biomedical applications. Ther. Innov. Regul. Sci. 54 , 308–317 (2020). 32072579 10.1007/s43441-019-00059-5 PMC7222141

624. Asar MC Franco A Soendergaard M Phage display selection, identification, and characterization of novel pancreatic cancer targeting peptides Biomolecules 2020 10 714 10.3390/biom10050714 32380649 PMC7277971 Asar, M. C., Franco, A. & Soendergaard, M. Phage display selection, identification, and characterization of novel pancreatic cancer targeting peptides. Biomolecules 10 , 714 (2020). 32380649 10.3390/biom10050714 PMC7277971

625. Bakhshinejad B Sadeghizadeh M Identification of a novel colon adenocarcinoma cell targeting peptide using phage display library biopanning Biotechnol. Appl. Biochem. 2022 69 2753 2765 10.1002/bab.2320 35103339 Bakhshinejad, B. & Sadeghizadeh, M. Identification of a novel colon adenocarcinoma cell targeting peptide using phage display library biopanning. Biotechnol. Appl. Biochem. 69 , 2753–2765 (2022). 35103339 10.1002/bab.2320

626. Li Y Yang K-d Duan H-y Phage-based peptides for pancreatic cancer diagnosis and treatment: Alternative approach Front. Microbiol. 2023 14 1231503 10.3389/fmicb.2023.1231503 37601380 PMC10433397 Li, Y., Yang, K.-d & Duan, H.-y Phage-based peptides for pancreatic cancer diagnosis and treatment: Alternative approach. Front. Microbiol. 14 , 1231503 (2023). 37601380 10.3389/fmicb.2023.1231503 PMC10433397

627. Chan SK Isolation of a peptide that binds to Pseudomonas aeruginosa lytic bacteriophage ACS omega 2022 7 38053 38060 10.1021/acsomega.2c05539 36312416 PMC9609082 Chan, S. K. et al. Isolation of a peptide that binds to Pseudomonas aeruginosa lytic bacteriophage. ACS omega 7 , 38053–38060 (2022). 36312416 10.1021/acsomega.2c05539 PMC9609082

628. Kelly M Peptide Probes of Colistin Resistance Discovered via Chemically Enhanced Phage Display ACS Infect. Dis. 2020 6 2410 2418 10.1021/acsinfecdis.0c00206 32786283 PMC8082519 Kelly, M. et al. Peptide Probes of Colistin Resistance Discovered via Chemically Enhanced Phage Display. ACS Infect. Dis. 6 , 2410–2418 (2020). 32786283 10.1021/acsinfecdis.0c00206 PMC8082519

629. Chen J Early detection of Alzheimer’s disease by peptides from phage display screening Brain Res 2019 1721 146306 10.1016/j.brainres.2019.146306 31247207 Chen, J. et al. Early detection of Alzheimer’s disease by peptides from phage display screening. Brain Res 1721 , 146306 (2019). 31247207 10.1016/j.brainres.2019.146306

630. Zhang X Zhang X Gao H Qing G Phage display derived peptides for alzheimer’s disease therapy and diagnosis Theranostics 2022 12 2041 10.7150/thno.68636 35265198 PMC8899571 Zhang, X., Zhang, X., Gao, H. & Qing, G. Phage display derived peptides for alzheimer’s disease therapy and diagnosis. Theranostics 12 , 2041 (2022). 35265198 10.7150/thno.68636 PMC8899571

631. Yu F Generation of a new therapeutic d-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway Cell Death Discov. 2024 10 51 10.1038/s41420-024-01822-w 38272890 PMC10810823 Yu, F. et al. Generation of a new therapeutic d-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway. Cell Death Discov. 10 , 51 (2024). 38272890 10.1038/s41420-024-01822-w PMC10810823

632. Heinis C Rutherford T Freund S Winter G Phage-encoded combinatorial chemical libraries based on bicyclic peptides Nat. Chem. Biol. 2009 5 502 507 10.1038/nchembio.184 19483697 Heinis, C., Rutherford, T., Freund, S. & Winter, G. Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat. Chem. Biol. 5 , 502–507 (2009). 19483697 10.1038/nchembio.184

633. França RK Progress on Phage Display Technology: Tailoring Antibodies for Cancer Immunotherapy Viruses 2023 15 1903 10.3390/v15091903 37766309 PMC10536222 França, R. K. et al. Progress on Phage Display Technology: Tailoring Antibodies for Cancer Immunotherapy. Viruses 15 , 1903 (2023). 37766309 10.3390/v15091903 PMC10536222

634. Hampton JT Novel regioselective approach to cyclize phage-displayed peptides in combination with epitope-directed selection to identify a potent neutralizing macrocyclic peptide for SARS-CoV-2 ACS Chem. Biol. 2022 17 2911 2922 10.1021/acschembio.2c00565 36174018 PMC9528030 Hampton, J. T. et al. Novel regioselective approach to cyclize phage-displayed peptides in combination with epitope-directed selection to identify a potent neutralizing macrocyclic peptide for SARS-CoV-2. ACS Chem. Biol. 17 , 2911–2922 (2022). 36174018 10.1021/acschembio.2c00565 PMC9528030

635. Gaynor KU Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2 Nat. Commun. 2023 14 3583 10.1038/s41467-023-39158-1 37328472 PMC10275983 Gaynor, K. U. et al. Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2. Nat. Commun. 14 , 3583 (2023). 37328472 10.1038/s41467-023-39158-1 PMC10275983

636. Li Z MYC-targeting inhibitors generated from a stereodiversified bicyclic peptide library J. Am. Chem. Soc. 2024 146 1356 1363 10.1021/jacs.3c09615 38170904 PMC10797614 Li, Z. et al. MYC-targeting inhibitors generated from a stereodiversified bicyclic peptide library. J. Am. Chem. Soc. 146 , 1356–1363 (2024). 38170904 10.1021/jacs.3c09615 PMC10797614

637. Andre AS Moutinho I Dias JNR Aires-da-Silva F In vivo Phage Display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties Front. Microbiol. 2022 13 962124 10.3389/fmicb.2022.962124 36225354 PMC9549074 Andre, A. S., Moutinho, I., Dias, J. N. R. & Aires-da-Silva, F. In vivo Phage Display: A promising selection strategy for the improvement of antibody targeting and drug delivery properties. Front. Microbiol. 13 , 962124 (2022). 36225354 10.3389/fmicb.2022.962124 PMC9549074

638. Hao L Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy J. Immunother. Cancer 2019 7 270 10.1186/s40425-019-0705-y 31640814 PMC6805442 Hao, L. et al. Discovery of low-molecular weight anti-PD-L1 peptides for cancer immunotherapy. J. Immunother. Cancer 7 , 270 (2019). 31640814 10.1186/s40425-019-0705-y PMC6805442

639. Hailing T Yonghong P Yufeng Z Haitao T Challenges for the application of EGFR-targeting peptide GE11 in tumor diagnosis and treatment J. Control. Release 2022 349 592 605 10.1016/j.jconrel.2022.07.018 35872181 Hailing, T., Yonghong, P., Yufeng, Z. & Haitao, T. Challenges for the application of EGFR-targeting peptide GE11 in tumor diagnosis and treatment. J. Control. Release 349 , 592–605 (2022). 35872181 10.1016/j.jconrel.2022.07.018

640. da Fonseca Alves R A novel peptide-based electrochemical biosensor for breast cancer characterization over a poly 3-(3-aminophenyl) propionic acid matrix Biosens. Bioelectron. 2022 205 114081 10.1016/j.bios.2022.114081 35217253 da Fonseca Alves, R. et al. A novel peptide-based electrochemical biosensor for breast cancer characterization over a poly 3-(3-aminophenyl) propionic acid matrix. Biosens. Bioelectron. 205 , 114081 (2022). 35217253 10.1016/j.bios.2022.114081

641. Kim H Jang JH Kim SC Cho JH Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa Eur. J. Med. Chem. 2020 185 111814 10.1016/j.ejmech.2019.111814 31678742 Kim, H., Jang, J. H., Kim, S. C. & Cho, J. H. Development of a novel hybrid antimicrobial peptide for targeted killing of Pseudomonas aeruginosa. Eur. J. Med. Chem. 185 , 111814 (2020). 31678742 10.1016/j.ejmech.2019.111814

642. Lee SY Choi JH Xu Z Microbial cell-surface display Trends Biotechnol. 2003 21 45 52 10.1016/S0167-7799(02)00006-9 12480350 Lee, S. Y., Choi, J. H. & Xu, Z. Microbial cell-surface display. Trends Biotechnol. 21 , 45–52 (2003). 12480350 10.1016/s0167-7799(02)00006-9

643. Lång H Outer membrane proteins as surface display systems Int. J. Med. Microbiol. 2000 290 579 585 10.1016/S1438-4221(00)80004-1 11200539 Lång, H. Outer membrane proteins as surface display systems. Int. J. Med. Microbiol. 290 , 579–585 (2000). 11200539 10.1016/S1438-4221(00)80004-1

644. Mahdavi SZB An overview on display systems (phage, bacterial, and yeast display) for production of anticancer antibodies; advantages and disadvantages Int. J. Biol. Macromol. 2022 208 421 442 10.1016/j.ijbiomac.2022.03.113 35339499 Mahdavi, S. Z. B. et al. An overview on display systems (phage, bacterial, and yeast display) for production of anticancer antibodies; advantages and disadvantages. Int. J. Biol. Macromol. 208 , 421–442 (2022). 35339499 10.1016/j.ijbiomac.2022.03.113

645. Csibra E Renders M Pinheiro VB Bacterial Cell Display as a Robust and Versatile Platform for Engineering Low‐Affinity Ligands and Enzymes ChemBioChem 2020 21 2844 2853 10.1002/cbic.202000203 32413179 PMC7586821 Csibra, E., Renders, M. & Pinheiro, V. B. Bacterial Cell Display as a Robust and Versatile Platform for Engineering Low‐Affinity Ligands and Enzymes. ChemBioChem 21 , 2844–2853 (2020). 32413179 10.1002/cbic.202000203 PMC7586821

646. Cioffi VB SARS-CoV-2 Spike protein peptides displayed in the Pyrococcus furiosus RAD system preserve epitopes antigenicity, immunogenicity, and virus-neutralizing activity of antibodies Sci. Rep. 2023 13 16821 10.1038/s41598-023-43720-8 37798298 PMC10556064 Cioffi, V. B. et al. SARS-CoV-2 Spike protein peptides displayed in the Pyrococcus furiosus RAD system preserve epitopes antigenicity, immunogenicity, and virus-neutralizing activity of antibodies. Sci. Rep. 13 , 16821 (2023). 37798298 10.1038/s41598-023-43720-8 PMC10556064

647. Li X-H Chavali PL Babu MM Capturing dynamic protein interactions Science 2018 359 1105 1106 10.1126/science.aat0576 29590031 Li, X.-H., Chavali, P. L. & Babu, M. M. Capturing dynamic protein interactions. Science 359 , 1105–1106 (2018). 29590031 10.1126/science.aat0576

648. Koh DW-S Tay J-H Gan SK-E Engineering Ag43 Signal Peptides with Bacterial Display and Selection Methods Protoc. 2022 6 1 10.3390/mps6010001 36648950 PMC9844295 Koh, D. W.-S., Tay, J.-H. & Gan, S. K.-E. Engineering Ag43 Signal Peptides with Bacterial Display and Selection. Methods Protoc. 6 , 1 (2022). 36648950 10.3390/mps6010001 PMC9844295

649. Zhao L Advances in the application of yeast surface display technology Chin. J. Biotechnol. 2023 39 4358 4375 10.13345/j.cjb.230085 38013172 Zhao, L. et al. Advances in the application of yeast surface display technology. Chin. J. Biotechnol. 39 , 4358–4375 (2023). 10.13345/j.cjb.230085 38013172

650. Cherf GM Cochran JR Applications of yeast surface display for protein engineering Methods Mol. Biol. 2015 1319 155 175 10.1007/978-1-4939-2748-7_8 26060074 PMC4544684 Cherf, G. M. & Cochran, J. R. Applications of yeast surface display for protein engineering. Methods Mol. Biol. 1319 , 155–175 (2015). 26060074 10.1007/978-1-4939-2748-7_8 PMC4544684

651. Shibasaki S Ueda M Progress of Molecular Display Technology Using Saccharomyces cerevisiae to Achieve Sustainable Development Goals Microorganisms 2023 11 125 10.3390/microorganisms11010125 36677416 PMC9864768 Shibasaki, S. & Ueda, M. Progress of Molecular Display Technology Using Saccharomyces cerevisiae to Achieve Sustainable Development Goals. Microorganisms 11 , 125 (2023). 36677416 10.3390/microorganisms11010125 PMC9864768

652. Zhang C Saccharomyces cerevisiae cell surface display technology: Strategies for improvement and applications Front Bioeng. Biotechnol. 2022 10 1056804 10.3389/fbioe.2022.1056804 36568309 PMC9767963 Zhang, C. et al. Saccharomyces cerevisiae cell surface display technology: Strategies for improvement and applications. Front Bioeng. Biotechnol. 10 , 1056804 (2022). 36568309 10.3389/fbioe.2022.1056804 PMC9767963

653. Lei H Yeast display platform technology to prepare oral vaccine against lethal H7N9 virus challenge in mice Microb. Cell. Fact. 2020 19 1 9 10.1186/s12934-020-01316-1 32122351 PMC7053147 Lei, H. et al. Yeast display platform technology to prepare oral vaccine against lethal H7N9 virus challenge in mice. Microb. Cell. Fact. 19 , 1–9 (2020). 32122351 10.1186/s12934-020-01316-1 PMC7053147

654. Kachroo AH Vandeloo M Greco BM Abdullah M Humanized yeast to model human biology, disease and evolution Dis. Model. Mech. 2022 15 dmm049309 10.1242/dmm.049309 35661208 PMC9194483 Kachroo, A. H., Vandeloo, M., Greco, B. M. & Abdullah, M. Humanized yeast to model human biology, disease and evolution. Dis. Model. Mech. 15 , dmm049309 (2022). 35661208 10.1242/dmm.049309 PMC9194483

655. Roohvand F Biomedical applications of yeasts-a patent view, part two: era of humanized yeasts and expanded applications Expert Opin. Ther. Pat. 2020 30 609 631 10.1080/13543776.2020.1781816 32529867 Roohvand, F. et al. Biomedical applications of yeasts-a patent view, part two: era of humanized yeasts and expanded applications. Expert Opin. Ther. Pat. 30 , 609–631 (2020). 32529867 10.1080/13543776.2020.1781816

656. Liu R Jiang W Mellins ED Yeast display of MHC-II enables rapid identification of peptide ligands from protein antigens (RIPPA) Cell. Mol. Immunol. 2021 18 1847 1860 10.1038/s41423-021-00717-5 34117370 PMC8193015 Liu, R., Jiang, W. & Mellins, E. D. Yeast display of MHC-II enables rapid identification of peptide ligands from protein antigens (RIPPA). Cell. Mol. Immunol. 18 , 1847–1860 (2021). 34117370 10.1038/s41423-021-00717-5 PMC8193015

657. Huisman BD Balivada PA Birnbaum ME Yeast display platform with expression of linear peptide epitopes for high-throughput assessment of peptide-MHC-II binding J. Biol. Chem. 2023 299 102913 10.1016/j.jbc.2023.102913 36649909 PMC9971316 Huisman, B. D., Balivada, P. A. & Birnbaum, M. E. Yeast display platform with expression of linear peptide epitopes for high-throughput assessment of peptide-MHC-II binding. J. Biol. Chem. 299 , 102913 (2023). 36649909 10.1016/j.jbc.2023.102913 PMC9971316

658. Priola JJ High‐throughput screening and selection of mammalian cells for enhanced protein production Biotechnol. J. 2016 11 853 865 10.1002/biot.201500579 27276699 Priola, J. J. et al. High‐throughput screening and selection of mammalian cells for enhanced protein production. Biotechnol. J. 11 , 853–865 (2016). 27276699 10.1002/biot.201500579

659. Liao KW Chou WC Lo YC Roffler SR Design of transgenes for efficient expression of active chimeric proteins on mammalian cells Biotechnol. Bioeng. 2001 73 313 323 10.1002/bit.1064 11283914 Liao, K. W., Chou, W. C., Lo, Y. C. & Roffler, S. R. Design of transgenes for efficient expression of active chimeric proteins on mammalian cells. Biotechnol. Bioeng. 73 , 313–323 (2001). 11283914 10.1002/bit.1064

660. Bowers PM Mammalian cell display for the discovery and optimization of antibody therapeutics Methods 2014 65 44 56 10.1016/j.ymeth.2013.06.010 23792919 Bowers, P. M. et al. Mammalian cell display for the discovery and optimization of antibody therapeutics. Methods 65 , 44–56 (2014). 23792919 10.1016/j.ymeth.2013.06.010

661. Robertson N Development of a novel mammalian display system for selection of antibodies against membrane proteins J. Biol. Chem. 2020 295 18436 18448 10.1074/jbc.RA120.015053 33127646 PMC7939478 Robertson, N. et al. Development of a novel mammalian display system for selection of antibodies against membrane proteins. J. Biol. Chem. 295 , 18436–18448 (2020). 33127646 10.1074/jbc.RA120.015053 PMC7939478

662. Huhtinen O Salbo R Lamminmäki U Prince S Selection of biophysically favorable antibody variants using a modified Flp-In CHO mammalian display platform Front Bioeng. Biotechnol. 2023 11 1170081 10.3389/fbioe.2023.1170081 37229492 PMC10203562 Huhtinen, O., Salbo, R., Lamminmäki, U. & Prince, S. Selection of biophysically favorable antibody variants using a modified Flp-In CHO mammalian display platform. Front Bioeng. Biotechnol. 11 , 1170081 (2023). 37229492 10.3389/fbioe.2023.1170081 PMC10203562

663. Li J Cell-Free Display Techniques for Protein Evolution Adv. Biochem. Eng. Biotechnol. 2023 185 59 90 37306697 10.1007/10_2023_227 Li, J. et al. Cell-Free Display Techniques for Protein Evolution. Adv. Biochem. Eng. Biotechnol. 185 , 59–90 (2023). 37306697 10.1007/10_2023_227

664. Kunamneni A Ogaugwu C Bradfute S Durvasula R Ribosome display technology: applications in disease diagnosis and control Antibodies 2020 9 28 10.3390/antib9030028 32605027 PMC7551589 Kunamneni, A., Ogaugwu, C., Bradfute, S. & Durvasula, R. Ribosome display technology: applications in disease diagnosis and control. Antibodies 9 , 28 (2020). 32605027 10.3390/antib9030028 PMC7551589

665. Ohoka A Sarkar CA Facile Display of Homomultivalent Proteins for In Vitro Selections ACS Synth. Biol. 2023 12 634 638 10.1021/acssynbio.2c00563 36655840 PMC9985468 Ohoka, A. & Sarkar, C. A. Facile Display of Homomultivalent Proteins for In Vitro Selections. ACS Synth. Biol. 12 , 634–638 (2023). 36655840 10.1021/acssynbio.2c00563 PMC9985468

666. Iskandar SE Identification of Covalent Cyclic Peptide Inhibitors in mRNA Display J. Am. Chem. Soc. 2023 145 15065 15070 10.1021/jacs.3c04833 37395736 PMC11246720 Iskandar, S. E. et al. Identification of Covalent Cyclic Peptide Inhibitors in mRNA Display. J. Am. Chem. Soc. 145 , 15065–15070 (2023). 37395736 10.1021/jacs.3c04833 PMC11246720

667. Mazón-Cabrera R Novel maternal autoantibodies in autism spectrum disorder: Implications for screening and diagnosis Front. Neurosci. 2023 17 1067833 10.3389/fnins.2023.1067833 36816132 PMC9932693 Mazón-Cabrera, R. et al. Novel maternal autoantibodies in autism spectrum disorder: Implications for screening and diagnosis. Front. Neurosci. 17 , 1067833 (2023). 36816132 10.3389/fnins.2023.1067833 PMC9932693

668. Patel S Mathonet P Jaulent AM Ullman CG Selection of a high-affinity WW domain against the extracellular region of VEGF receptor isoform-2 from a combinatorial library using CIS display Protein Eng. Des. Sel. 2013 26 307 315 10.1093/protein/gzt003 23378640 Patel, S., Mathonet, P., Jaulent, A. M. & Ullman, C. G. Selection of a high-affinity WW domain against the extracellular region of VEGF receptor isoform-2 from a combinatorial library using CIS display. Protein Eng. Des. Sel. 26 , 307–315 (2013). 23378640 10.1093/protein/gzt003

669. Thakur R Suri CR Kaur IP Rishi P Peptides as diagnostic, therapeutic, and theranostic tools: progress and future challenges Crit. Rev. Ther. Drug Carr. Syst. 2023 40 49 100 10.1615/CritRevTherDrugCarrierSyst.2022040322 36374841 Thakur, R., Suri, C. R., Kaur, I. P. & Rishi, P. Peptides as diagnostic, therapeutic, and theranostic tools: progress and future challenges. Crit. Rev. Ther. Drug Carr. Syst. 40 , 49–100 (2023). 10.1615/CritRevTherDrugCarrierSyst.2022040322 36374841

670. Sharma K Sharma KK Sharma A Jain R Peptide-based drug discovery: Current status and recent advances Drug Discov. Today 2023 28 103464 10.1016/j.drudis.2022.103464 36481586 Sharma, K., Sharma, K. K., Sharma, A. & Jain, R. Peptide-based drug discovery: Current status and recent advances. Drug Discov. Today 28 , 103464 (2023). 36481586 10.1016/j.drudis.2022.103464

671. Zhang H Deep Learning-Based Bioactive Therapeutic Peptide Generation and Screening J. Chem. Inf. Model. 2023 63 835 845 10.1021/acs.jcim.2c01485 36724090 Zhang, H. et al. Deep Learning-Based Bioactive Therapeutic Peptide Generation and Screening. J. Chem. Inf. Model. 63 , 835–845 (2023). 36724090 10.1021/acs.jcim.2c01485

672. Parvatikar PP Artificial intelligence: Machine learning approach for screening large database and drug discovery Antivir. Res 2023 220 105740 10.1016/j.antiviral.2023.105740 37935248 Parvatikar, P. P. et al. Artificial intelligence: Machine learning approach for screening large database and drug discovery. Antivir. Res 220 , 105740 (2023). 37935248 10.1016/j.antiviral.2023.105740

673. Sarkar C Artificial Intelligence and Machine Learning Technology Driven Modern Drug Discovery and Development Int. J. Mol. Sci. 2023 24 2026 10.3390/ijms24032026 36768346 PMC9916967 Sarkar, C. et al. Artificial Intelligence and Machine Learning Technology Driven Modern Drug Discovery and Development. Int. J. Mol. Sci. 24 , 2026 (2023). 36768346 10.3390/ijms24032026 PMC9916967

674. Zhang Y Deep learning drives efficient discovery of novel antihypertensive peptides from soybean protein isolate Food Chem. 2023 404 134690 10.1016/j.foodchem.2022.134690 36323032 Zhang, Y. et al. Deep learning drives efficient discovery of novel antihypertensive peptides from soybean protein isolate. Food Chem. 404 , 134690 (2023). 36323032 10.1016/j.foodchem.2022.134690

675. Kumar SA Machine learning and deep learning in data-driven decision making of drug discovery and challenges in high-quality data acquisition in the pharmaceutical industry Future Med. Chem. 2021 14 245 270 10.4155/fmc-2021-0243 34939433 Kumar, S. A. et al. Machine learning and deep learning in data-driven decision making of drug discovery and challenges in high-quality data acquisition in the pharmaceutical industry. Future Med. Chem. 14 , 245–270 (2021). 34939433 10.4155/fmc-2021-0243

676. Wu X Lin H Bai R Duan H Deep learning for advancing peptide drug development: Tools and methods in structure prediction and design Eur. J. Med. Chem. 2024 268 116262 10.1016/j.ejmech.2024.116262 38387334 Wu, X., Lin, H., Bai, R. & Duan, H. Deep learning for advancing peptide drug development: Tools and methods in structure prediction and design. Eur. J. Med. Chem. 268 , 116262 (2024). 38387334 10.1016/j.ejmech.2024.116262

677. Cesaro A Deep learning tools to accelerate antibiotic discovery Expert Opin. Drug Dis. 2023 18 1245 1257 10.1080/17460441.2023.2250721 PMC10790350 37794737 Cesaro, A. et al. Deep learning tools to accelerate antibiotic discovery. Expert Opin. Drug Dis. 18 , 1245–1257 (2023). 10.1080/17460441.2023.2250721 PMC10790350 37794737

678. Cao Q Designing antimicrobial peptides using deep learning and molecular dynamic simulations Brief. Bioinform. 2023 24 bbad058 10.1093/bib/bbad058 36857616 Cao, Q. et al. Designing antimicrobial peptides using deep learning and molecular dynamic simulations. Brief. Bioinform. 24 , bbad058 (2023). 36857616 10.1093/bib/bbad058

679. Ge R Dong C Wang J Wei Y Machine learning for peptide structure, function, and design Front. Genet. 2022 13 1007635 10.3389/fgene.2022.1007635 36204314 PMC9531310 Ge, R., Dong, C., Wang, J. & Wei, Y. Machine learning for peptide structure, function, and design. Front. Genet. 13 , 1007635 (2022). 36204314 10.3389/fgene.2022.1007635 PMC9531310

680. Li C Machine Learning Guides Peptide Nucleic Acid Flow Synthesis and Sequence Design Adv. Sci. 2022 9 2201988 10.1002/advs.202201988 PMC9731686 36270977 Li, C. et al. Machine Learning Guides Peptide Nucleic Acid Flow Synthesis and Sequence Design. Adv. Sci. 9 , 2201988 (2022). 10.1002/advs.202201988 PMC9731686 36270977

681. Bryant P Elofsson A Peptide binder design with inverse folding and protein structure prediction Comm. Chem. 2023 6 229 10.1038/s42004-023-01029-7 PMC10600234 37880344 Bryant, P. & Elofsson, A. Peptide binder design with inverse folding and protein structure prediction. Comm. Chem. 6 , 229 (2023). 10.1038/s42004-023-01029-7 PMC10600234 37880344

682. Vidal-Limon A Aguilar-Toalá JE Liceaga AM Integration of Molecular Docking Analysis and Molecular Dynamics Simulations for Studying Food Proteins and Bioactive Peptides J. Agric. Food Chem. 2022 70 934 943 10.1021/acs.jafc.1c06110 34990125 Vidal-Limon, A., Aguilar-Toalá, J. E. & Liceaga, A. M. Integration of Molecular Docking Analysis and Molecular Dynamics Simulations for Studying Food Proteins and Bioactive Peptides. J. Agric. Food Chem. 70 , 934–943 (2022). 34990125 10.1021/acs.jafc.1c06110

683. Guterres H Im W Improving Protein-Ligand Docking Results with High-Throughput Molecular Dynamics Simulations J. Chem. Inf. Model. 2020 60 2189 2198 10.1021/acs.jcim.0c00057 32227880 PMC7534544 Guterres, H. & Im, W. Improving Protein-Ligand Docking Results with High-Throughput Molecular Dynamics Simulations. J. Chem. Inf. Model. 60 , 2189–2198 (2020). 32227880 10.1021/acs.jcim.0c00057 PMC7534544

684. Wang B Razavi S Gamazon ER Towards mechanistic models of mutational effects: Deep learning on Alzheimer’s Aβ peptide Comp. Struct. Biotechnol. J. 2023 21 2434 2445 10.1016/j.csbj.2023.03.051 PMC10114515 37090430 Wang, B., Razavi, S. & Gamazon, E. R. Towards mechanistic models of mutational effects: Deep learning on Alzheimer’s Aβ peptide. Comp. Struct. Biotechnol. J. 21 , 2434–2445 (2023). 10.1016/j.csbj.2023.03.051 PMC10114515 37090430

685. Bolatchiev A Baturin V Shchetinin E Bolatchieva E Novel Antimicrobial Peptides Designed Using a Recurrent Neural Network Reduce Mortality in Experimental Sepsis Antibiotics. lElectroencephalography Clin. Neurophysiol. Suppl. 2022 11 411 10.3390/antibiotics11030411 PMC8944797 35326874 Bolatchiev, A., Baturin, V., Shchetinin, E. & Bolatchieva, E. Novel Antimicrobial Peptides Designed Using a Recurrent Neural Network Reduce Mortality in Experimental Sepsis. Antibiotics. lElectroencephalography Clin. Neurophysiol. Suppl. 11 , 411 (2022). 10.3390/antibiotics11030411 PMC8944797 35326874

686. Szymczak P Discovering highly potent antimicrobial peptides with deep generative model HydrAMP Nat. Commun. 2023 14 1453 10.1038/s41467-023-36994-z 36922490 PMC10017685 Szymczak, P. et al. Discovering highly potent antimicrobial peptides with deep generative model HydrAMP. Nat. Commun. 14 , 1453 (2023). 36922490 10.1038/s41467-023-36994-z PMC10017685

687. Prykhodko O A de novo molecular generation method using latent vector based generative adversarial network J. Cheminform. 2019 11 74 10.1186/s13321-019-0397-9 33430938 PMC6892210 Prykhodko, O. et al. A de novo molecular generation method using latent vector based generative adversarial network. J. Cheminform. 11 , 74 (2019). 33430938 10.1186/s13321-019-0397-9 PMC6892210

688. Xie X Valiente PA Kim PM HelixGAN a deep-learning methodology for conditional de novo design of α-helix structures Bioinformatics 2023 39 btad036 10.1093/bioinformatics/btad036 36651657 PMC9887083 Xie, X., Valiente, P. A. & Kim, P. M. HelixGAN a deep-learning methodology for conditional de novo design of α-helix structures. Bioinformatics 39 , btad036 (2023). 36651657 10.1093/bioinformatics/btad036 PMC9887083

689. Vázquez Torres S De novo design of high-affinity binders of bioactive helical peptides Nature 2024 626 435 442 10.1038/s41586-023-06953-1 38109936 PMC10849960 Vázquez Torres, S. et al. De novo design of high-affinity binders of bioactive helical peptides. Nature 626 , 435–442 (2024). 38109936 10.1038/s41586-023-06953-1 PMC10849960

690. Mihalič F Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets Nat. Commun. 2023 14 5636 10.1038/s41467-023-41312-8 37704626 PMC10499821 Mihalič, F. et al. Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets. Nat. Commun. 14 , 5636 (2023). 37704626 10.1038/s41467-023-41312-8 PMC10499821

691. Cao L Design of protein-binding proteins from the target structure alone Nature 2022 605 551 560 10.1038/s41586-022-04654-9 35332283 PMC9117152 Cao, L. et al. Design of protein-binding proteins from the target structure alone. Nature 605 , 551–560 (2022). 35332283 10.1038/s41586-022-04654-9 PMC9117152

692. Kolluri S Machine learning and artificial intelligence in pharmaceutical research and development: a review AAPS J. 2022 24 1 10 10.1208/s12248-021-00644-3 PMC8726514 34984579 Kolluri, S. et al. Machine learning and artificial intelligence in pharmaceutical research and development: a review. AAPS J. 24 , 1–10 (2022). 10.1208/s12248-021-00644-3 PMC8726514 34984579

693. Khan SR Al Rijjal D Piro A Wheeler MB Integration of AI and traditional medicine in drug discovery Drug Discov. Today 2021 26 982 992 10.1016/j.drudis.2021.01.008 33476566 Khan, S. R., Al Rijjal, D., Piro, A. & Wheeler, M. B. Integration of AI and traditional medicine in drug discovery. Drug Discov. Today 26 , 982–992 (2021). 33476566 10.1016/j.drudis.2021.01.008

694. Thakur A Application of Artificial Intelligence in Pharmaceutical and Biomedical Studies Curr. Pharm. Des. 2020 26 3569 3578 10.2174/1381612826666200515131245 32410553 Thakur, A. et al. Application of Artificial Intelligence in Pharmaceutical and Biomedical Studies. Curr. Pharm. Des. 26 , 3569–3578 (2020). 32410553 10.2174/1381612826666200515131245

695. Ching T Opportunities and obstacles for deep learning in biology and medicine J. R. Soc. Interface 2018 15 20170387 10.1098/rsif.2017.0387 29618526 PMC5938574 Ching, T. et al. Opportunities and obstacles for deep learning in biology and medicine. J. R. Soc. Interface 15 , 20170387 (2018). 29618526 10.1098/rsif.2017.0387 PMC5938574

696. Stahlschmidt SR Ulfenborg B Synnergren J Multimodal deep learning for biomedical data fusion: a review Brief. Bioinform. 2022 23 bbab569 10.1093/bib/bbab569 35089332 PMC8921642 Stahlschmidt, S. R., Ulfenborg, B. & Synnergren, J. Multimodal deep learning for biomedical data fusion: a review. Brief. Bioinform. 23 , bbab569 (2022). 35089332 10.1093/bib/bbab569 PMC8921642

697. Candemir S Nguyen XV Folio LR Prevedello LM Training Strategies for Radiology Deep Learning Models in Data-limited Scenarios Radio. Artif. Intell. 2021 3 e210014 10.1148/ryai.2021210014 PMC8637222 34870217 Candemir, S., Nguyen, X. V., Folio, L. R. & Prevedello, L. M. Training Strategies for Radiology Deep Learning Models in Data-limited Scenarios. Radio. Artif. Intell. 3 , e210014 (2021). 10.1148/ryai.2021210014 PMC8637222 34870217

698. Menghani G Efficient deep learning: A survey on making deep learning models smaller, faster, and better ACM Comput. Surv. 2023 55 1 37 10.1145/3578938 Menghani, G. Efficient deep learning: A survey on making deep learning models smaller, faster, and better. ACM Comput. Surv. 55 , 1–37 (2023).

699. Mitragotri S Burke PA Langer R Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies Nat. Rev. Drug Discov. 2014 13 655 672 10.1038/nrd4363 25103255 PMC4455970 Mitragotri, S., Burke, P. A. & Langer, R. Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nat. Rev. Drug Discov. 13 , 655–672 (2014). 25103255 10.1038/nrd4363 PMC4455970

700. Yuan X Smart delivery of poly-peptide composite for effective cancer therapy Biomed. Mater. 2022 17 024103 10.1088/1748-605X/ac494c 34996052 Yuan, X. et al. Smart delivery of poly-peptide composite for effective cancer therapy. Biomed. Mater. 17 , 024103 (2022). 10.1088/1748-605X/ac494c 34996052

701. Dombu CY Betbeder D Airway delivery of peptides and proteins using nanoparticles Biomaterials 2013 34 516 525 10.1016/j.biomaterials.2012.08.070 23046753 Dombu, C. Y. & Betbeder, D. Airway delivery of peptides and proteins using nanoparticles. Biomaterials 34 , 516–525 (2013). 23046753 10.1016/j.biomaterials.2012.08.070

702. Zapadka KL Becher FJ Gomes dos Santos AL Jackson SE Factors affecting the physical stability (aggregation) of peptide therapeutics Interface Focus 2017 7 20170030 10.1098/rsfs.2017.0030 29147559 PMC5665799 Zapadka, K. L., Becher, F. J., Gomes dos Santos, A. L. & Jackson, S. E. Factors affecting the physical stability (aggregation) of peptide therapeutics. Interface Focus 7 , 20170030 (2017). 29147559 10.1098/rsfs.2017.0030 PMC5665799

703. Sharma G Nanoparticle based insulin delivery system: the next generation efficient therapy for Type 1 diabetes J. Nanobiotechnol. 2015 13 74 10.1186/s12951-015-0136-y PMC4619439 26498972 Sharma, G. et al. Nanoparticle based insulin delivery system: the next generation efficient therapy for Type 1 diabetes. J. Nanobiotechnol. 13 , 74 (2015). 10.1186/s12951-015-0136-y PMC4619439 26498972

704. Collins DS Sánchez-Félix M Badkar AV Mrsny R Accelerating the development of novel technologies and tools for the subcutaneous delivery of biotherapeutics J. Control. Release 2020 321 475 482 10.1016/j.jconrel.2020.02.036 32105759 Collins, D. S., Sánchez-Félix, M., Badkar, A. V. & Mrsny, R. Accelerating the development of novel technologies and tools for the subcutaneous delivery of biotherapeutics. J. Control. Release 321 , 475–482 (2020). 32105759 10.1016/j.jconrel.2020.02.036

705. Li C Advances in Subcutaneous Delivery Systems of Biomacromolecular Agents for Diabetes Treatment Int. J. Nanomed. 2021 16 1261 1280 10.2147/IJN.S283416 PMC7898203 33628020 Li, C. et al. Advances in Subcutaneous Delivery Systems of Biomacromolecular Agents for Diabetes Treatment. Int. J. Nanomed. 16 , 1261–1280 (2021). 10.2147/IJN.S283416 PMC7898203 33628020

706. Su Y PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application Drug Deliv. 2021 28 1397 1418 10.1080/10717544.2021.1938756 34184949 PMC8248937 Su, Y. et al. PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application. Drug Deliv. 28 , 1397–1418 (2021). 34184949 10.1080/10717544.2021.1938756 PMC8248937

707. Qiu Y Park K Environment-sensitive hydrogels for drug delivery Adv. Drug Del. Rev. 2001 53 321 339 10.1016/S0169-409X(01)00203-4 11744175 Qiu, Y. & Park, K. Environment-sensitive hydrogels for drug delivery. Adv. Drug Del. Rev. 53 , 321–339 (2001). 10.1016/s0169-409x(01)00203-4 11744175

708. Barlek MH Systemic peptide amphiphile nanofiber delivery following subcutaneous injection Biomaterials 2023 303 122401 10.1016/j.biomaterials.2023.122401 38006645 Barlek, M. H. et al. Systemic peptide amphiphile nanofiber delivery following subcutaneous injection. Biomaterials 303 , 122401 (2023). 38006645 10.1016/j.biomaterials.2023.122401

709. Du M Establishment of ultrasound-responsive SonoBacteriaBot for targeted drug delivery and controlled release Front Bioeng. Biotechnol. 2023 11 1144963 10.3389/fbioe.2023.1144963 36911192 PMC9998949 Du, M. et al. Establishment of ultrasound-responsive SonoBacteriaBot for targeted drug delivery and controlled release. Front Bioeng. Biotechnol. 11 , 1144963 (2023). 36911192 10.3389/fbioe.2023.1144963 PMC9998949

710. Yi X Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound Int. J. Pharm. 2023 643 123266 10.1016/j.ijpharm.2023.123266 37482226 Yi, X. et al. Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound. Int. J. Pharm. 643 , 123266 (2023). 37482226 10.1016/j.ijpharm.2023.123266

711. Chen G Oral delivery of protein and peptide drugs: From non-specific formulation approaches to intestinal cell targeting strategies Theranostics 2022 12 1419 10.7150/thno.61747 35154498 PMC8771547 Chen, G. et al. Oral delivery of protein and peptide drugs: From non-specific formulation approaches to intestinal cell targeting strategies. Theranostics 12 , 1419 (2022). 35154498 10.7150/thno.61747 PMC8771547

712. Sams L Characterization of pepsin from rabbit gastric extract, its action on β-casein and the effects of lipids on proteolysis Food Funct. 2018 9 5975 5988 10.1039/C8FO01450G 30379166 Sams, L. et al. Characterization of pepsin from rabbit gastric extract, its action on β-casein and the effects of lipids on proteolysis. Food Funct. 9 , 5975–5988 (2018). 30379166 10.1039/c8fo01450g

713. Tornøe CW Johansson E Wahlund P-O Divergent Protein Synthesis of Bowman–Birk Protease Inhibitors, their Hydrodynamic Behavior and Co-crystallization with α-Chymotrypsin Synlett 2017 28 1901 1906 10.1055/s-0036-1588840 Tornøe, C. W., Johansson, E. & Wahlund, P.-O. Divergent Protein Synthesis of Bowman–Birk Protease Inhibitors, their Hydrodynamic Behavior and Co-crystallization with α-Chymotrypsin. Synlett 28 , 1901–1906 (2017).

714. Wang H Feng Z Xu B D-amino acid-containing supramolecular nanofibers for potential cancer therapeutics Adv. Drug Del. Rev. 2017 110-111 102 111 10.1016/j.addr.2016.04.008 PMC5071117 27102943 Wang, H., Feng, Z. & Xu, B. D-amino acid-containing supramolecular nanofibers for potential cancer therapeutics. Adv. Drug Del. Rev. 110-111 , 102–111 (2017). 10.1016/j.addr.2016.04.008 PMC5071117 27102943

715. Wang J Strategies for improving the safety and RNAi efficacy of noncovalent peptide/siRNA nanocomplexes Adv. Colloid Interface Sci. 2022 302 102638 10.1016/j.cis.2022.102638 35299136 Wang, J. et al. Strategies for improving the safety and RNAi efficacy of noncovalent peptide/siRNA nanocomplexes. Adv. Colloid Interface Sci. 302 , 102638 (2022). 35299136 10.1016/j.cis.2022.102638

716. Shinga K L17ER4: A cell-permeable attenuated cationic amphiphilic lytic peptide Biorg. Med. Chem. 2022 61 116728 10.1016/j.bmc.2022.116728 35395514 Shinga, K. et al. L17ER4: A cell-permeable attenuated cationic amphiphilic lytic peptide. Biorg. Med. Chem. 61 , 116728 (2022). 10.1016/j.bmc.2022.116728 35395514

717. Meier-Menches SM Casini A Design Strategies and Medicinal Applications of Metal-Peptidic Bioconjugates Bioconjugate Chem. 2020 31 1279 1288 10.1021/acs.bioconjchem.0c00152 32243752 Meier-Menches, S. M. & Casini, A. Design Strategies and Medicinal Applications of Metal-Peptidic Bioconjugates. Bioconjugate Chem. 31 , 1279–1288 (2020). 10.1021/acs.bioconjchem.0c00152 32243752

718. Hayes HC Luk LYP Tsai Y-H Approaches for peptide and protein cyclisation Org. Biomol. Chem. 2021 19 3983 4001 10.1039/D1OB00411E 33978044 PMC8114279 Hayes, H. C., Luk, L. Y. P. & Tsai, Y.-H. Approaches for peptide and protein cyclisation. Org. Biomol. Chem. 19 , 3983–4001 (2021). 33978044 10.1039/d1ob00411e PMC8114279

719. Naylor MR Bockus AT Blanco M-J Lokey RS Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets Curr. Opin. Chem. Biol. 2017 38 141 147 10.1016/j.cbpa.2017.04.012 28570865 Naylor, M. R., Bockus, A. T., Blanco, M.-J. & Lokey, R. S. Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Curr. Opin. Chem. Biol. 38 , 141–147 (2017). 28570865 10.1016/j.cbpa.2017.04.012

720. He J Folic acid-modified reverse micelle-lipid nanocapsules overcome intestinal barriers and improve the oral delivery of peptides Drug Deliv. 2023 30 2181744 10.1080/10717544.2023.2181744 36855953 PMC9980025 He, J. et al. Folic acid-modified reverse micelle-lipid nanocapsules overcome intestinal barriers and improve the oral delivery of peptides. Drug Deliv. 30 , 2181744 (2023). 36855953 10.1080/10717544.2023.2181744 PMC9980025

721. Stähelin HF The history of cyclosporin A (Sandimmune®) revisited: Another point of view Experientia 1996 52 5 13 10.1007/BF01922409 8575558 Stähelin, H. F. The history of cyclosporin A (Sandimmune®) revisited: Another point of view. Experientia 52 , 5–13 (1996). 8575558 10.1007/BF01922409

722. Bhardwaj G Accurate de novo design of membrane-traversing macrocycles Cell 2022 185 3520 3532 10.1016/j.cell.2022.07.019 36041435 PMC9490236 Bhardwaj, G. et al. Accurate de novo design of membrane-traversing macrocycles. Cell 185 , 3520–3532 (2022). 36041435 10.1016/j.cell.2022.07.019 PMC9490236

723. Zheng Y Cong Y Schmidt EW Nair SK Catalysts for the Enzymatic Lipidation of Peptides Acc. Chem. Res. 2022 55 1313 1323 10.1021/acs.accounts.2c00108 35442036 PMC9519032 Zheng, Y., Cong, Y., Schmidt, E. W. & Nair, S. K. Catalysts for the Enzymatic Lipidation of Peptides. Acc. Chem. Res. 55 , 1313–1323 (2022). 35442036 10.1021/acs.accounts.2c00108 PMC9519032

724. Berg S Considerations in the developability of peptides for oral administration when formulated together with transient permeation enhancers Int. J. Pharm. 2022 628 122238 10.1016/j.ijpharm.2022.122238 36174850 Berg, S. et al. Considerations in the developability of peptides for oral administration when formulated together with transient permeation enhancers. Int. J. Pharm. 628 , 122238 (2022). 36174850 10.1016/j.ijpharm.2022.122238

725. Falanga A The world of cell penetrating: the future of medical applications Future Med. Chem. 2020 12 1431 1446 10.4155/fmc-2020-0140 32723097 Falanga, A. et al. The world of cell penetrating: the future of medical applications. Future Med. Chem. 12 , 1431–1446 (2020). 32723097 10.4155/fmc-2020-0140

726. Sanjanwala D Polysaccharide-based hydrogels for drug delivery and wound management: a review Expert Opin. Drug Deliv. 2022 19 1664 1695 10.1080/17425247.2022.2152791 36440488 Sanjanwala, D. et al. Polysaccharide-based hydrogels for drug delivery and wound management: a review. Expert Opin. Drug Deliv. 19 , 1664–1695 (2022). 36440488 10.1080/17425247.2022.2152791

727. Doostmohammadi M Hydrogels For Peptide Hormones Delivery: Therapeutic And Tissue Engineering Applications Drug Des. Devel. Ther. 2019 13 3405 3418 10.2147/DDDT.S217211 31579238 PMC6770672 Doostmohammadi, M. et al. Hydrogels For Peptide Hormones Delivery: Therapeutic And Tissue Engineering Applications. Drug Des. Devel. Ther. 13 , 3405–3418 (2019). 31579238 10.2147/DDDT.S217211 PMC6770672

728. Biermasz NR New medical therapies on the horizon: oral octreotide Pituitary 2017 20 149 153 10.1007/s11102-016-0785-3 28091879 PMC5334421 Biermasz, N. R. New medical therapies on the horizon: oral octreotide. Pituitary 20 , 149–153 (2017). 28091879 10.1007/s11102-016-0785-3 PMC5334421

729. Dubey SK Oral peptide delivery: challenges and the way ahead Drug Discov. Today 2021 26 931 950 10.1016/j.drudis.2021.01.001 33444788 Dubey, S. K. et al. Oral peptide delivery: challenges and the way ahead. Drug Discov. Today 26 , 931–950 (2021). 33444788 10.1016/j.drudis.2021.01.001

730. Knudsen LB Lau J The discovery and development of liraglutide and semaglutide Front. Endocrinol. 2019 10 155 10.3389/fendo.2019.00155 PMC6474072 31031702 Knudsen, L. B. & Lau, J. The discovery and development of liraglutide and semaglutide. Front. Endocrinol. 10 , 155 (2019). 10.3389/fendo.2019.00155 PMC6474072 31031702

731. Tucker TJ A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors J. Med. Chem. 2021 64 16770 16800 10.1021/acs.jmedchem.1c01599 34704436 Tucker, T. J. et al. A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors. J. Med. Chem. 64 , 16770–16800 (2021). 34704436 10.1021/acs.jmedchem.1c01599

732. Hunt NJ Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia Nat. Nanotechnol. 2024 19 534 544 10.1038/s41565-023-01565-2 38168926 PMC11026164 Hunt, N. J. et al. Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia. Nat. Nanotechnol. 19 , 534–544 (2024). 38168926 10.1038/s41565-023-01565-2 PMC11026164

733. Kaffash E Shahbazi M-A Hatami H Nokhodchi A An insight into gastrointestinal macromolecule delivery using physical oral devices Drug Discov. Today 2022 27 2309 2321 10.1016/j.drudis.2022.04.014 35460891 Kaffash, E., Shahbazi, M.-A., Hatami, H. & Nokhodchi, A. An insight into gastrointestinal macromolecule delivery using physical oral devices. Drug Discov. Today 27 , 2309–2321 (2022). 35460891 10.1016/j.drudis.2022.04.014

734. Chellappan DK Protein and peptide delivery to lungs by using advanced targeted drug delivery Chem. -Biol. Interact. 2022 351 109706 10.1016/j.cbi.2021.109706 34662570 Chellappan, D. K. et al. Protein and peptide delivery to lungs by using advanced targeted drug delivery. Chem. -Biol. Interact. 351 , 109706 (2022). 34662570 10.1016/j.cbi.2021.109706

735. Sanchit A Recent Advances in Delivery of Peptide and Protein Therapeutics to the Brain J. Pharmacol. Exp. Ther. 2024 388 54 10.1124/jpet.123.001690 37977811 Sanchit, A. et al. Recent Advances in Delivery of Peptide and Protein Therapeutics to the Brain. J. Pharmacol. Exp. Ther. 388 , 54 (2024). 37977811 10.1124/jpet.123.001690

736. Zhang T Luo X Xu K Zhong W Peptide-containing nanoformulations: Skin barrier penetration and activity contribution Adv. Drug Del. Rev. 2023 203 115139 10.1016/j.addr.2023.115139 37951358 Zhang, T., Luo, X., Xu, K. & Zhong, W. Peptide-containing nanoformulations: Skin barrier penetration and activity contribution. Adv. Drug Del. Rev. 203 , 115139 (2023). 10.1016/j.addr.2023.115139 37951358

737. Attia SA MacKay JA Protein and polypeptide mediated delivery to the eye Adv. Drug Del. Rev. 2022 188 114441 10.1016/j.addr.2022.114441 PMC10049092 35817213 Attia, S. A. & MacKay, J. A. Protein and polypeptide mediated delivery to the eye. Adv. Drug Del. Rev. 188 , 114441 (2022). 10.1016/j.addr.2022.114441 PMC10049092 35817213

738. Montgomery J Connexin 43-Based Therapeutics for Dermal Wound Healing Int. J. Mol. Sci. 2018 19 1778 10.3390/ijms19061778 29914066 PMC6032231 Montgomery, J. et al. Connexin 43-Based Therapeutics for Dermal Wound Healing. Int. J. Mol. Sci. 19 , 1778 (2018). 29914066 10.3390/ijms19061778 PMC6032231

739. Alavi SE Cabot PJ Moyle PM Glucagon-like peptide-1 receptor agonists and strategies to improve their efficiency Mol. Pharm. 2019 16 2278 2295 10.1021/acs.molpharmaceut.9b00308 31050435 Alavi, S. E., Cabot, P. J. & Moyle, P. M. Glucagon-like peptide-1 receptor agonists and strategies to improve their efficiency. Mol. Pharm. 16 , 2278–2295 (2019). 31050435 10.1021/acs.molpharmaceut.9b00308

740. Wauters L Joly F Treatment of short bowel syndrome: Breaking the therapeutic ceiling? Nutr. Clin. Pract. 2023 38 S76 S87 10.1002/ncp.10974 37115030 Wauters, L. & Joly, F. Treatment of short bowel syndrome: Breaking the therapeutic ceiling? Nutr. Clin. Pract. 38 , S76–S87 (2023). 37115030 10.1002/ncp.10974

741. Fan X Ocular therapies with biomacromolecules: From local injection to eyedrop and emerging noninvasive delivery strategies Adv. Drug Del. Rev. 2023 197 114864 10.1016/j.addr.2023.114864 37156266 Fan, X. et al. Ocular therapies with biomacromolecules: From local injection to eyedrop and emerging noninvasive delivery strategies. Adv. Drug Del. Rev. 197 , 114864 (2023). 10.1016/j.addr.2023.114864 37156266

742. Apovian CM McDonnell ME CagriSema and the link between obesity and type 2 diabetes Lancet 2023 402 671 673 10.1016/S0140-6736(23)01291-6 37364591 Apovian, C. M. & McDonnell, M. E. CagriSema and the link between obesity and type 2 diabetes. Lancet 402 , 671–673 (2023). 37364591 10.1016/S0140-6736(23)01291-6

743. Bassetti M Del Puente F Magnasco L Giacobbe DR Innovative therapies for acute bacterial skin and skin-structure infections (ABSSSI) caused by methicillin-resistant Staphylococcus aureus: advances in phase I and II trials Expert Opin. Investig. Drugs 2020 29 495 506 10.1080/13543784.2020.1750595 32242469 Bassetti, M., Del Puente, F., Magnasco, L. & Giacobbe, D. R. Innovative therapies for acute bacterial skin and skin-structure infections (ABSSSI) caused by methicillin-resistant Staphylococcus aureus: advances in phase I and II trials. Expert Opin. Investig. Drugs 29 , 495–506 (2020). 32242469 10.1080/13543784.2020.1750595

744. Guo W Discovery of ecnoglutide-a novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog Mol. Metab. 2023 75 101762 10.1016/j.molmet.2023.101762 37364710 PMC10339203 Guo, W. et al. Discovery of ecnoglutide-a novel, long-acting, cAMP-biased glucagon-like peptide-1 (GLP-1) analog. Mol. Metab. 75 , 101762 (2023). 37364710 10.1016/j.molmet.2023.101762 PMC10339203

745. Takacs I An Open-label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism J. Clin. Endocrinol. Metab. 2024 109 2199 2209 10.1210/clinem/dgae121 38449442 Takacs, I. et al. An Open-label Phase 2 Study of Eneboparatide, a Novel PTH Receptor 1 Agonist, in Hypoparathyroidism. J. Clin. Endocrinol. Metab. 109 , 2199–2209 (2024). 38449442 10.1210/clinem/dgae121

746. Güzelburç V Noktüri: Değerlendirme ve Tedavi Kontinans ve N.öroüroloji Bülteni 2019 6 15 12 Güzelburç, V. Noktüri: Değerlendirme ve Tedavi. Kontinans ve N.öroüroloji Bülteni 6 , 15–12 (2019).

747. Hvistendahl MK Effect of glepaglutide, a long‐acting glucagon‐like peptide‐2 analog, on gastrointestinal transit time and motility in patients with short bowel syndrome: findings from a randomized trial J. Parenter. Enter. Nutr. 2020 44 1535 1544 10.1002/jpen.1767 32022286 Hvistendahl, M. K. et al. Effect of glepaglutide, a long‐acting glucagon‐like peptide‐2 analog, on gastrointestinal transit time and motility in patients with short bowel syndrome: findings from a randomized trial. J. Parenter. Enter. Nutr. 44 , 1535–1544 (2020). 10.1002/jpen.1767 32022286

748. Liakos A Karagiannis T Tsapas A In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk Ann. Intern. Med. 2024 177 JC6 10.7326/J23-0110 38163368 Liakos, A., Karagiannis, T. & Tsapas, A. In T2DM requiring insulin initiation, icodec titrated with an app safely reduced HbA1c vs. daily basal insulin analogues at 52 wk. Ann. Intern. Med. 177 , JC6 (2024). 38163368 10.7326/J23-0110

749. Bettonville M Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan GF 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study BMC Musculoskelet. Disord. 2021 22 1 15 10.1186/s12891-021-04750-3 34666767 PMC8527807 Bettonville, M. et al. Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan GF 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study. BMC Musculoskelet. Disord. 22 , 1–15 (2021). 34666767 10.1186/s12891-021-04750-3 PMC8527807

750. Harisseh R Delale T Yeh M Allas S SUN-609 Livoletide (AZP-531), an Unacylated Ghrelin Analogue, Improves Hyperphagia and Food-Related Behaviors Both in Obese and Non-Obese People with Prader-Willi Syndrome J. Endocr. Soc. 2020 4 SUN-609 10.1210/jendso/bvaa046.1004 Harisseh, R., Delale, T., Yeh, M. & Allas, S. SUN-609 Livoletide (AZP-531), an Unacylated Ghrelin Analogue, Improves Hyperphagia and Food-Related Behaviors Both in Obese and Non-Obese People with Prader-Willi Syndrome. J. Endocr. Soc. 4 , SUN-609 (2020).

751. François B Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial Intensive Care Med 2020 46 1425 1437 10.1007/s00134-020-06109-z 32468087 François, B. et al. Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial. Intensive Care Med 46 , 1425–1437 (2020). 32468087 10.1007/s00134-020-06109-z

752. Hill MD Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial Lancet 2020 395 878 887 10.1016/S0140-6736(20)30258-0 32087818 Hill, M. D. et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet 395 , 878–887 (2020). 32087818 10.1016/S0140-6736(20)30258-0

753. Flamm RK Rhomberg PR Farrell DJ Jones RN In vitro spectrum of pexiganan activity; bactericidal action and resistance selection tested against pathogens with elevated MIC values to topical agents Diagn. Microbiol. Infect. Dis. 2016 86 66 69 10.1016/j.diagmicrobio.2016.06.012 27352729 Flamm, R. K., Rhomberg, P. R., Farrell, D. J. & Jones, R. N. In vitro spectrum of pexiganan activity; bactericidal action and resistance selection tested against pathogens with elevated MIC values to topical agents. Diagn. Microbiol. Infect. Dis. 86 , 66–69 (2016). 27352729 10.1016/j.diagmicrobio.2016.06.012

754. Camilleri M Efficacy and safety of relamorelin in diabetics with symptoms of gastroparesis: a randomized, placebo-controlled study Gastroenterology 2017 153 1240 1250 10.1053/j.gastro.2017.07.035 28760384 PMC5670003 Camilleri, M. et al. Efficacy and safety of relamorelin in diabetics with symptoms of gastroparesis: a randomized, placebo-controlled study. Gastroenterology 153 , 1240–1250 (2017). 28760384 10.1053/j.gastro.2017.07.035 PMC5670003

755. Sun Y Leung VY Cheung KM Clinical trials of intervertebral disc regeneration: current status and future developments Int. Orthop. 2019 43 1003 1010 10.1007/s00264-018-4245-8 30498908 Sun, Y., Leung, V. Y. & Cheung, K. M. Clinical trials of intervertebral disc regeneration: current status and future developments. Int. Orthop. 43 , 1003–1010 (2019). 30498908 10.1007/s00264-018-4245-8

756. Jastreboff AM Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial N. Engl. J. Med. 2023 389 514 526 10.1056/NEJMoa2301972 37366315 Jastreboff, A. M. et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N. Engl. J. Med. 389 , 514–526 (2023). 37366315 10.1056/NEJMoa2301972

757. Qian-yu L Ling-Qian DU Tian D Shao-hua GE Effects of exenatide-4 on proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells Shanghai J. Stomatol. 2020 29 225 33043336 Qian-yu, L., Ling-Qian, D. U., Tian, D. & Shao-hua, G. E. Effects of exenatide-4 on proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells. Shanghai J. Stomatol. 29 , 225 (2020). 33043336

758. Verstovsek S A phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera Blood 2021 138 1504 10.1182/blood-2021-149219 Verstovsek, S. et al. A phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood 138 , 1504 (2021).34010392

759. Chen TK Hoenig MP Nitsch D Grams ME Advances in the management of chronic kidney disease BMJ 2023 383 e074216 10.1136/bmj-2022-074216 38052474 Chen, T. K., Hoenig, M. P., Nitsch, D. & Grams, M. E. Advances in the management of chronic kidney disease. BMJ 383 , e074216 (2023). 38052474 10.1136/bmj-2022-074216

760. Nakagami H Investigator‐initiated clinical study of a functional peptide, SR‐0379, for limb ulcers of patients with Werner syndrome as a pilot study Geriatr. Gerontol. Int. 2019 19 1118 1123 10.1111/ggi.13782 31746528 Nakagami, H. et al. Investigator‐initiated clinical study of a functional peptide, SR‐0379, for limb ulcers of patients with Werner syndrome as a pilot study. Geriatr. Gerontol. Int. 19 , 1118–1123 (2019). 31746528 10.1111/ggi.13782

761. le Roux CW Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial Lancet Diabetes Endocrinol. 2024 12 162 173 10.1016/S2213-8587(23)00356-X 38330987 le Roux, C. W. et al. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol. 12 , 162–173 (2024). 38330987 10.1016/S2213-8587(23)00356-X

762. Yu Z New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease Front. Med. 2022 9 937142 10.3389/fmed.2022.937142 PMC9453230 36091713 Yu, Z. et al. New, potent, small molecule agonists of tyrosine kinase receptors attenuate dry eye disease. Front. Med. 9 , 937142 (2022). 10.3389/fmed.2022.937142 PMC9453230 36091713

763. Cabri W Therapeutic peptides targeting PPI in clinical development: Overview, mechanism of action and perspectives Front. Mol. Biosci. 2021 8 697586 10.3389/fmolb.2021.697586 34195230 PMC8236712 Cabri, W. et al. Therapeutic peptides targeting PPI in clinical development: Overview, mechanism of action and perspectives. Front. Mol. Biosci. 8 , 697586 (2021). 34195230 10.3389/fmolb.2021.697586 PMC8236712

764. Al-Horani RA Kar S Potential anti-SARS-CoV-2 therapeutics that target the post-entry stages of the viral life cycle: A comprehensive review Viruses 2020 12 1092 10.3390/v12101092 32993173 PMC7600245 Al-Horani, R. A. & Kar, S. Potential anti-SARS-CoV-2 therapeutics that target the post-entry stages of the viral life cycle: A comprehensive review. Viruses 12 , 1092 (2020). 32993173 10.3390/v12101092 PMC7600245

765. Al Wadi K Ghatage P Efficacy of trebananib (AMG 386) in treating epithelial ovarian cancer Expert Opin. Pharmacother. 2016 17 853 860 10.1517/14656566.2016.1161027 26933765 Al Wadi, K. & Ghatage, P. Efficacy of trebananib (AMG 386) in treating epithelial ovarian cancer. Expert Opin. Pharmacother. 17 , 853–860 (2016). 26933765 10.1517/14656566.2016.1161027

766. Packer M Effect of ularitide on cardiovascular mortality in acute heart failure N. Engl. J. Med. 2017 376 1956 1964 10.1056/NEJMoa1601895 28402745 Packer, M. et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N. Engl. J. Med. 376 , 1956–1964 (2017). 28402745 10.1056/NEJMoa1601895

767. Bourhis J Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design Future Oncol. 2022 18 1669 1678 10.2217/fon-2021-1634 35172587 Bourhis, J. et al. Xevinapant or placebo plus chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck: TrilynX phase III study design. Future Oncol. 18 , 1669–1678 (2022). 35172587 10.2217/fon-2021-1634

768. Guidotti G Brambilla L Rossi D Peptides in clinical development for the treatment of brain tumors Curr. Opin. Pharmacol. 2019 47 102 109 10.1016/j.coph.2019.02.007 30959356 Guidotti, G., Brambilla, L. & Rossi, D. Peptides in clinical development for the treatment of brain tumors. Curr. Opin. Pharmacol. 47 , 102–109 (2019). 30959356 10.1016/j.coph.2019.02.007

769. Staecker H Efficacy and safety of AM-111 in the treatment of acute unilateral sudden deafness—A double-blind, randomized, placebo-controlled phase 3 study Otol. Neurotol. 2019 40 584 10.1097/MAO.0000000000002229 31083077 PMC6553962 Staecker, H. et al. Efficacy and safety of AM-111 in the treatment of acute unilateral sudden deafness—A double-blind, randomized, placebo-controlled phase 3 study. Otol. Neurotol. 40 , 584 (2019). 31083077 10.1097/MAO.0000000000002229 PMC6553962

770. Miyaji Y Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats Drug Metab. Disposition. 2011 39 1946 1953 10.1124/dmd.111.040725 21712433 Miyaji, Y. et al. Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats. Drug Metab. Disposition. 39 , 1946–1953 (2011). 10.1124/dmd.111.040725 21712433

771. Cousins MJ The safety and efficacy of KAI-1678—an inhibitor of epsilon protein kinase C (εPKC)—versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design Pain. Med 2013 14 533 540 10.1111/pme.12058 23438341 Cousins, M. J. et al. The safety and efficacy of KAI-1678—an inhibitor of epsilon protein kinase C (εPKC)—versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. Pain. Med 14 , 533–540 (2013). 23438341 10.1111/pme.12058

772. Miampamba M Sensitive in vivo visualization of breast cancer using ratiometric protease-activatable fluorescent imaging agent, AVB-620 Theranostics 2017 7 3369 10.7150/thno.20678 28900516 PMC5595138 Miampamba, M. et al. Sensitive in vivo visualization of breast cancer using ratiometric protease-activatable fluorescent imaging agent, AVB-620. Theranostics 7 , 3369 (2017). 28900516 10.7150/thno.20678 PMC5595138

773. Chiquet C Postoperative ocular inflammation: a single subconjunctival injection of XG-102 compared to dexamethasone drops in a randomized trial Am. J. Ophthalmol. 2017 174 76 84 10.1016/j.ajo.2016.10.012 27810317 Chiquet, C. et al. Postoperative ocular inflammation: a single subconjunctival injection of XG-102 compared to dexamethasone drops in a randomized trial. Am. J. Ophthalmol. 174 , 76–84 (2017). 27810317 10.1016/j.ajo.2016.10.012

774. Coriat R Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study Int. J. Nanomed. 2016 11 6207 6216 10.2147/IJN.S110274 PMC5123727 27920527 Coriat, R. et al. Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study. Int. J. Nanomed. 11 , 6207–6216 (2016). 10.2147/IJN.S110274 PMC5123727 27920527

775. Saleh MN Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53 Clin. Cancer Res. 2021 27 5236 5247 10.1158/1078-0432.CCR-21-0715 34301750 PMC9401461 Saleh, M. N. et al. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53. Clin. Cancer Res. 27 , 5236–5247 (2021). 34301750 10.1158/1078-0432.CCR-21-0715 PMC9401461

776. Guerlavais V Discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide in clinical development J. Med. Chem. 2023 66 9401 9417 10.1021/acs.jmedchem.3c00623 37439511 Guerlavais, V. et al. Discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide in clinical development. J. Med. Chem. 66 , 9401–9417 (2023). 37439511 10.1021/acs.jmedchem.3c00623

777. Young CC Vedadghavami A Bajpayee AG Bioelectricity for drug delivery: the promise of cationic therapeutics Bioelectricity 2020 2 68 81 10.1089/bioe.2020.0012 32803148 PMC7313641 Young, C. C., Vedadghavami, A. & Bajpayee, A. G. Bioelectricity for drug delivery: the promise of cationic therapeutics. Bioelectricity 2 , 68–81 (2020). 32803148 10.1089/bioe.2020.0012 PMC7313641

778. Sun T Visible-light-driven photo-Fenton oxidation enhanced by Fe/Bi-nanocrystal phase transformation as a universal way for various organic pollutants mineralization Chem. Eng. J. 2024 481 148732 10.1016/j.cej.2024.148732 Sun, T. et al. Visible-light-driven photo-Fenton oxidation enhanced by Fe/Bi-nanocrystal phase transformation as a universal way for various organic pollutants mineralization. Chem. Eng. J. 481 , 148732 (2024).

779. Lopes LB Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-β1-induced CTGF expression in keloid fibroblasts J. Invest. Dermatol. 2009 129 590 598 10.1038/jid.2008.264 18787533 PMC2740368 Lopes, L. B. et al. Cell permeant peptide analogues of the small heat shock protein, HSP20, reduce TGF-β1-induced CTGF expression in keloid fibroblasts. J. Invest. Dermatol. 129 , 590–598 (2009). 18787533 10.1038/jid.2008.264 PMC2740368

780. Weemering DN A randomized, double‐blind, placebo‐controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis Eur. J. Neurol. 2023 30 3722 3731 10.1111/ene.16020 37550954 Weemering, D. N. et al. A randomized, double‐blind, placebo‐controlled phase 2 study to assess safety, tolerability, and efficacy of RT001 in patients with amyotrophic lateral sclerosis. Eur. J. Neurol. 30 , 3722–3731 (2023). 37550954 10.1111/ene.16020

781. Zesiewicz T Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich’s ataxia Mov. Disord. 2018 33 1000 1005 10.1002/mds.27353 29624723 Zesiewicz, T. et al. Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich’s ataxia. Mov. Disord. 33 , 1000–1005 (2018). 29624723 10.1002/mds.27353

782. Garcia-Murray E Safety and efficacy of RT002, an injectable botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study Dermatol. Surg. 2015 41 S47 S55 10.1097/DSS.0000000000000276 25548845 Garcia-Murray, E. et al. Safety and efficacy of RT002, an injectable botulinum toxin type A, for treating glabellar lines: results of a phase 1/2, open-label, sequential dose-escalation study. Dermatol. Surg. 41 , S47–S55 (2015). 25548845 10.1097/DSS.0000000000000276

783. Kinali M Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study Lancet Neurol. 2009 8 918 928 10.1016/S1474-4422(09)70211-X 19713152 PMC2755039 Kinali, M. et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 8 , 918–928 (2009). 19713152 10.1016/S1474-4422(09)70211-X PMC2755039

784. Doss JT Jr Topical Phosphorodiamidate Morpholino Oligomer Antisense Compounds Effectivly Delay Cornea Rejection in a Transplant Rat Model Invest. Ophthalmol. Vis. Sci. 2008 49 5764 5764 Doss, J. T. Jr et al. Topical Phosphorodiamidate Morpholino Oligomer Antisense Compounds Effectivly Delay Cornea Rejection in a Transplant Rat Model. Invest. Ophthalmol. Vis. Sci. 49 , 5764–5764 (2008).

785. Hosseini A Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model J. Ocul. Pharmacol. Ther. 2012 28 194 201 10.1089/jop.2011.0135 22149555 Hosseini, A. et al. Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model. J. Ocul. Pharmacol. Ther. 28 , 194–201 (2012). 22149555 10.1089/jop.2011.0135

786. Su F Bovine HDL and dual domain HDL-mimetic peptides inhibit tumor development in mice J. Cancer Res. Ther. 2020 8 101 10.17303/jcrto.2020.8.101 PMC7252215 32462055 Su, F. et al. Bovine HDL and dual domain HDL-mimetic peptides inhibit tumor development in mice. J. Cancer Res. Ther. 8 , 101 (2020). 10.17303/jcrto.2020.8.101 PMC7252215 32462055

787. Jauset T Beaulieu M-E Bioactive cell penetrating peptides and proteins in cancer: a bright future ahead Curr. Opin. Pharmacol. 2019 47 133 140 10.1016/j.coph.2019.03.014 31048179 Jauset, T. & Beaulieu, M.-E. Bioactive cell penetrating peptides and proteins in cancer: a bright future ahead. Curr. Opin. Pharmacol. 47 , 133–140 (2019). 31048179 10.1016/j.coph.2019.03.014

788. Farhat R The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice Cancer Res 2023 83 6129 6129 10.1158/1538-7445.AM2023-6129 Farhat, R. et al. The proapoptotic peptide PEP-010 is efficient on several models of different tumor origins and it can be monitored by pharmacodynamic biomarker candidates in clinical practice. Cancer Res 83 , 6129–6129 (2023).

789. Kumthekar P ANG1005, a brain-penetrating peptide–drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases Clin. Cancer Res. 2020 26 2789 2799 10.1158/1078-0432.CCR-19-3258 31969331 Kumthekar, P. et al. ANG1005, a brain-penetrating peptide–drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clin. Cancer Res. 26 , 2789–2799 (2020). 31969331 10.1158/1078-0432.CCR-19-3258

790. Bates S ANG-1005 in Patients with Brain Metastases from Breast Cancer: Correlative Imaging with 18F-FLT-PET/CT Ann. Oncol. 2015 26 ii20 10.1093/annonc/mdv091.1 Bates, S. et al. ANG-1005 in Patients with Brain Metastases from Breast Cancer: Correlative Imaging with 18F-FLT-PET/CT. Ann. Oncol. 26 , ii20 (2015).

791. Bennett G Development of BT1718, a Bicycle Drug Conjugate®(BDC) targeting MT1-MMP for treatment of solid tumours Eur. J. Cancer 2016 69 S21 10.1016/S0959-8049(16)32642-9 Bennett, G. et al. Development of BT1718, a Bicycle Drug Conjugate®(BDC) targeting MT1-MMP for treatment of solid tumours. Eur. J. Cancer 69 , S21 (2016).

792. Bennett G MMAE delivery using the bicycle toxin conjugate BT5528 Mol. Cancer Ther. 2020 19 1385 1394 10.1158/1535-7163.MCT-19-1092 32398269 Bennett, G. et al. MMAE delivery using the bicycle toxin conjugate BT5528. Mol. Cancer Ther. 19 , 1385–1394 (2020). 32398269 10.1158/1535-7163.MCT-19-1092

793. Currie J-C The peptide-drug conjugate th1902: a new sortilin receptor-mediated cancer therapeutic against ovarian and endometrial cancers Cancers (Basel) 2022 14 1877 10.3390/cancers14081877 35454785 PMC9031804 Currie, J.-C. et al. The peptide-drug conjugate th1902: a new sortilin receptor-mediated cancer therapeutic against ovarian and endometrial cancers. Cancers (Basel) 14 , 1877 (2022). 35454785 10.3390/cancers14081877 PMC9031804

794. Demeule M Increasing potency of anticancer drugs through sortilin receptor-mediated cancer therapy: a new targeted approach for the treatment of ovarian cancer Cancer Res 2020 80 1061 1061 10.1158/1538-7445.AM2020-1061 Demeule, M. et al. Increasing potency of anticancer drugs through sortilin receptor-mediated cancer therapy: a new targeted approach for the treatment of ovarian cancer. Cancer Res 80 , 1061–1061 (2020).

795. Mahalingam D A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma Cancers (Basel) 2019 11 833 10.3390/cancers11060833 31212948 PMC6627768 Mahalingam, D. et al. A phase II, multicenter, single-arm study of mipsagargin (G-202) as a second-line therapy following sorafenib for adult patients with progressive advanced hepatocellular carcinoma. Cancers (Basel) 11 , 833 (2019). 31212948 10.3390/cancers11060833 PMC6627768

796. Gregorc V NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial Lancet Oncol. 2018 19 799 811 10.1016/S1470-2045(18)30193-1 29753703 Gregorc, V. et al. NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 19 , 799–811 (2018). 29753703 10.1016/S1470-2045(18)30193-1

797. Berdel WE Animal safety, toxicology, and pharmacokinetic studies according to the ICH S9 guideline for a novel fusion protein tTF-NGR targeting procoagulatory activity into tumor vasculature: Are results predictive for humans? Cancers (Basel) 2020 12 3536 10.3390/cancers12123536 33256235 PMC7759859 Berdel, W. E. et al. Animal safety, toxicology, and pharmacokinetic studies according to the ICH S9 guideline for a novel fusion protein tTF-NGR targeting procoagulatory activity into tumor vasculature: Are results predictive for humans? Cancers (Basel) 12 , 3536 (2020). 33256235 10.3390/cancers12123536 PMC7759859

798. Halperin DM The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results J. Clin. Oncol. 2021 39 4110 4110 10.1200/JCO.2021.39.15_suppl.4110 Halperin, D. M. et al. The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results. J. Clin. Oncol. 39 , 4110–4110 (2021).

799. Gründker C Wokoun U Hellriegel M Emons G Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells J. Obstet. Gynaecol. Res. 2019 45 1334 1342 10.1111/jog.13980 31016845 Gründker, C., Wokoun, U., Hellriegel, M. & Emons, G. Inhibition of aerobic glycolysis enhances the anti‐tumor efficacy of Zoptarelin Doxorubicin in triple‐negative breast cancer cells. J. Obstet. Gynaecol. Res. 45 , 1334–1342 (2019). 31016845 10.1111/jog.13980

800. Gong J First-in-human, phase I study of CBP-1008, a bi-specific ligand drug conjugate, in patients with advanced solid tumors J. Clin. Oncol. 2023 41 5577 5577 10.1200/JCO.2023.41.16_suppl.5577 Gong, J. et al. First-in-human, phase I study of CBP-1008, a bi-specific ligand drug conjugate, in patients with advanced solid tumors. J. Clin. Oncol. 41 , 5577–5577 (2023).

801. Rice C The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13 Cancer Res. 2018 78 1936 1936 10.1158/1538-7445.AM2018-1936 Rice, C. et al. The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13. Cancer Res. 78 , 1936–1936 (2018).

802. Pauwels E 18F-AlF-NOTA-octreotide outperforms 68Ga-DOTATATE/NOC PET in neuroendocrine tumor patients: results from a prospective, multicenter study J. Nucl. Med. 2023 64 632 638 10.2967/jnumed.122.264563 36265911 Pauwels, E. et al. 18F-AlF-NOTA-octreotide outperforms 68Ga-DOTATATE/NOC PET in neuroendocrine tumor patients: results from a prospective, multicenter study. J. Nucl. Med. 64 , 632–638 (2023). 36265911 10.2967/jnumed.122.264563

803. Carlsen EA Prospective phase II trial of [68Ga] Ga-NODAGA-E [c (RGDyK)] 2 PET/CT imaging of integrin αvβ3 for prognostication in patients with neuroendocrine neoplasms J. Nucl. Med. 2023 64 252 259 10.2967/jnumed.122.264383 35981899 PMC9902862 Carlsen, E. A. et al. Prospective phase II trial of [68Ga] Ga-NODAGA-E [c (RGDyK)] 2 PET/CT imaging of integrin αvβ3 for prognostication in patients with neuroendocrine neoplasms. J. Nucl. Med. 64 , 252–259 (2023). 35981899 10.2967/jnumed.122.264383 PMC9902862

804. Menda Y 90Y-DOTATOC dosimetry–based personalized peptide receptor radionuclide therapy J. Nucl. Med. 2018 59 1692 1698 10.2967/jnumed.117.202903 29523629 PMC6225542 Menda, Y. et al. 90Y-DOTATOC dosimetry–based personalized peptide receptor radionuclide therapy. J. Nucl. Med. 59 , 1692–1698 (2018). 29523629 10.2967/jnumed.117.202903 PMC6225542

805. Xiao L Xin J Advances in Clinical Oncology Research on 99mTc-3PRGD2 SPECT Imaging Front. Oncol. 2022 12 898764 10.3389/fonc.2022.898764 35712468 PMC9195171 Xiao, L. & Xin, J. Advances in Clinical Oncology Research on 99mTc-3PRGD2 SPECT Imaging. Front. Oncol. 12 , 898764 (2022). 35712468 10.3389/fonc.2022.898764 PMC9195171

806. Deppen SA 68Ga-DOTATATE compared with 111In-DTPA-octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis J. Nucl. Med. 2016 57 872 878 10.2967/jnumed.115.165803 26769864 PMC5362941 Deppen, S. A. et al. 68Ga-DOTATATE compared with 111In-DTPA-octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis. J. Nucl. Med. 57 , 872–878 (2016). 26769864 10.2967/jnumed.115.165803 PMC5362941

807. Gayle S Antigen-independent tumor targeting by CBX-12 (alphalex™–exatecan) induces long-term antitumor immunity Immunotherapy 2022 14 1467 1480 10.2217/imt-2022-0121 36597724 Gayle, S. et al. Antigen-independent tumor targeting by CBX-12 (alphalex™–exatecan) induces long-term antitumor immunity. Immunotherapy 14 , 1467–1480 (2022). 36597724 10.2217/imt-2022-0121

808. Harris E Industry News October 2020 Ther. Deliv. 2021 12 111 117 10.4155/tde-2020-0126 33455454 Harris, E. Industry News October 2020. Ther. Deliv. 12 , 111–117 (2021). 33455454 10.4155/tde-2020-0126

809. Marsolais C A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer Cancer Res 2020 80 2910 2910 10.1158/1538-7445.AM2020-2910 Marsolais, C. et al. A novel Sortilin-targeted docetaxel peptide conjugate (TH1902), for the treatment of Sortilin-positive (SORT1+) triple-negative breast cancer. Cancer Res 80 , 2910–2910 (2020).

810. Kilk K Langel U Cellular delivery of peptide nucleic acid by cell-penetrating peptides Methods Mol. Biol. 2005 298 131 141 16044544 10.1385/1-59259-877-3:131 Kilk, K. & Langel, U. Cellular delivery of peptide nucleic acid by cell-penetrating peptides. Methods Mol. Biol. 298 , 131–141 (2005). 16044544 10.1385/1-59259-877-3:131

811. Bou-Samra P Intraoperative molecular imaging: 3rd biennial clinical trials update J. Biomed. Opt. 2023 28 050901 050901 10.1117/1.JBO.28.5.050901 37193364 PMC10182831 Bou-Samra, P. et al. Intraoperative molecular imaging: 3rd biennial clinical trials update. J. Biomed. Opt. 28 , 050901–050901 (2023). 37193364 10.1117/1.JBO.28.5.050901 PMC10182831

812. Chelariu-Raicu A A multicenter open-label randomized phase II trial of paclitaxel plus EP-100, a novel LHRH receptor-targeted, membrane-disrupting peptide, versus paclitaxel alone for refractory or recurrent ovarian cancer Gynecol. Oncol. 2021 160 418 426 10.1016/j.ygyno.2020.11.013 33243443 Chelariu-Raicu, A. et al. A multicenter open-label randomized phase II trial of paclitaxel plus EP-100, a novel LHRH receptor-targeted, membrane-disrupting peptide, versus paclitaxel alone for refractory or recurrent ovarian cancer. Gynecol. Oncol. 160 , 418–426 (2021). 33243443 10.1016/j.ygyno.2020.11.013

813. Jin M Ramdomized 3-armed phase III study of S-1 monotherapy versus S-1/CDDP (SP) versus 5-FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC-101 study J. Clin. Oncol. 2008 26 4533 4533 10.1200/jco.2008.26.15_suppl.4533 Jin, M. et al. Ramdomized 3-armed phase III study of S-1 monotherapy versus S-1/CDDP (SP) versus 5-FU/CDDP (FP) in patients (pts) with advanced gastric cancer (AGC): SC-101 study. J. Clin. Oncol. 26 , 4533–4533 (2008).

814. Steven SY A phase II trial of AEZS-108 in castration-and taxane-resistant prostate cancer Clin. Genitourin. Cancer 2017 15 742 749 10.1016/j.clgc.2017.06.002 28668277 Steven, S. Y. et al. A phase II trial of AEZS-108 in castration-and taxane-resistant prostate cancer. Clin. Genitourin. Cancer 15 , 742–749 (2017). 28668277 10.1016/j.clgc.2017.06.002

815. Kolahdouzan M Futhey NC Kieran NW Healy LM Novel molecular leads for the prevention of damage and the promotion of repair in neuroimmunological disease Front. Immunol. 2019 10 1657 10.3389/fimmu.2019.01657 31379852 PMC6658885 Kolahdouzan, M., Futhey, N. C., Kieran, N. W. & Healy, L. M. Novel molecular leads for the prevention of damage and the promotion of repair in neuroimmunological disease. Front. Immunol. 10 , 1657 (2019). 31379852 10.3389/fimmu.2019.01657 PMC6658885

816. Fujimaki T P07. 02 Trials of a personalized peptide vaccine (ITK-1) for patients with recurrent or progressive glioblastoma (GBM) Neuro Oncol. 2017 19 iii52 10.1093/neuonc/nox036.187 Fujimaki, T. et al. P07. 02 Trials of a personalized peptide vaccine (ITK-1) for patients with recurrent or progressive glioblastoma (GBM). Neuro Oncol. 19 , iii52 (2017).

817. McDermott D Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20) Ann. Oncol. 2013 24 2694 2698 10.1093/annonc/mdt291 23942774 McDermott, D. et al. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann. Oncol. 24 , 2694–2698 (2013). 23942774 10.1093/annonc/mdt291

818. Manning-Geist BL Phase I study of a multivalent WT1 peptide vaccine (Galinpepimut-S) in combination with nivolumab in patients with WT1-expressing ovarian cancer in second or third remission Cancers (Basel) 2023 15 1458 10.3390/cancers15051458 36900251 PMC10001251 Manning-Geist, B. L. et al. Phase I study of a multivalent WT1 peptide vaccine (Galinpepimut-S) in combination with nivolumab in patients with WT1-expressing ovarian cancer in second or third remission. Cancers (Basel) 15 , 1458 (2023). 36900251 10.3390/cancers15051458 PMC10001251

819. Lorentzen CL Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab J. Immunother. Cancer 2023 11 e006755 10.1136/jitc-2023-006755 37217243 PMC10230976 Lorentzen, C. L. et al. Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab. J. Immunother. Cancer 11 , e006755 (2023). 37217243 10.1136/jitc-2023-006755 PMC10230976

820. Patel S 353TiP Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2+ GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 Ann. Oncol. 2023 34 S323 10.1016/j.annonc.2023.09.3080 Patel, S. et al. 353TiP Phase III study to evaluate the efficacy and safety of GLSI-100 (GP2+ GM-CSF) in breast cancer patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01. Ann. Oncol. 34 , S323 (2023).

821. Daiko H Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients Cancer Immunol. Immunother. 2020 69 2247 2257 10.1007/s00262-020-02619-3 32500232 PMC7568713 Daiko, H. et al. Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients. Cancer Immunol. Immunother. 69 , 2247–2257 (2020). 32500232 10.1007/s00262-020-02619-3 PMC7568713

822. Gilliam A Watson S G17DT: an antigastrin immunogen for the treatment of gastrointestinal malignancy Expert Opin. Biol. Ther. 2007 7 397 404 10.1517/14712598.7.3.397 17309331 Gilliam, A. & Watson, S. G17DT: an antigastrin immunogen for the treatment of gastrointestinal malignancy. Expert Opin. Biol. Ther. 7 , 397–404 (2007). 17309331 10.1517/14712598.7.3.397

823. Schneble EJ The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response Immunotherapy 2014 6 519 531 10.2217/imt.14.22 24896623 Schneble, E. J. et al. The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response. Immunotherapy 6 , 519–531 (2014). 24896623 10.2217/imt.14.22

824. Wurz GT Kao C-J Wolf M DeGregorio MW Tecemotide: an antigen-specific cancer immunotherapy Hum. Vaccin. Immunother. 2014 10 3383 3393 10.4161/hv.29836 25483673 PMC4514140 Wurz, G. T., Kao, C.-J., Wolf, M. & DeGregorio, M. W. Tecemotide: an antigen-specific cancer immunotherapy. Hum. Vaccin. Immunother. 10 , 3383–3393 (2014). 25483673 10.4161/hv.29836 PMC4514140

825. Murahashi M Investigator initiated clinical trial of cancer vaccine OCV-C01 in advanced and recurrent biliary tract cancer Ann. Oncol. 2018 29 vii60 10.1093/annonc/mdy374.040 Murahashi, M. et al. Investigator initiated clinical trial of cancer vaccine OCV-C01 in advanced and recurrent biliary tract cancer. Ann. Oncol. 29 , vii60 (2018).

826. Habib AA Ahmadi Jazi G Mozaffar T Update on immune‐mediated therapies for myasthenia gravis Muscle Nerve 2020 62 579 592 10.1002/mus.26919 32462710 Habib, A. A., Ahmadi Jazi, G. & Mozaffar, T. Update on immune‐mediated therapies for myasthenia gravis. Muscle Nerve 62 , 579–592 (2020). 32462710 10.1002/mus.26919