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State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a highly evolved histidyl-hydrazide structure in the treatment and therapeutic management of a group of sight-threatening eye diseases.

OBJECTIVE: The exact biological functions of the aminoacyl-histidine dipeptides in ophthalmology are still unknown but they are the subject of intensive research activities at Innovative Vision Products, Inc. (IVP). Numerous studies have demonstrated, both at the tissue and organelle levels, that naturally occuring imidazole containing peptidomimetics possess strong and specific antioxidant properties, by preventing and reducing the accumulation of oxidised products derived from the lipid peroxidation (LPO) of biological membranes. Carnosine has been shown to act as a competitive inhibitor of …

CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model.

BACKGROUND: Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Early administration of prophylactic antibiotics is known to improve outcomes; however, increasing concern regarding antimicrobial resistance makes finding new compounds for use in such cases a pressing area for further research. CSA-90, a synthetic peptidomimetic compound, has previously demonstrated promising antimicrobial action against Staphylococcus aureus in rat open fractures. However, its efficacy against antibiotic-resistant microorganisms, its potential as a therapeut

Chemical Patterns of Proteasome Inhibitors: Lessons Learned from Two Decades of Drug Design.

Drug discovery now faces a new challenge, where the availability of experimental data is no longer the limiting step, and instead, making sense of the data has gained a new level of importance, propelled by the extensive incorporation of cheminformatics and bioinformatics methodologies into the drug discovery and development pipeline. These enable, for example, the inference of structure-activity relationships that can be useful in the discovery of new drug candidates. One of the therapeutic applications that could benefit from this type of data mining is proteasome inhibition, given that mult

The γ-secretase complex: from discovery to a therapeutic target.

γ-Secretase is an intricate intramembrane aspartyl protease that cleaves within the transmembrane domain of ∼150 substrates and is considered the 'proteasome of the membrane'. This enzyme consists of four different subunits, with presenilin being the catalytic subunit. This review provides a brief overview of γ-secretase as a proteolytic enzyme, from its biochemistry and biology to its roles in disease and potential as a therapeutic target. A detailed discussion on the discovery and structure of γ-secretase is followed by a survey of its substrates, including the most studied amyloid precursor

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… Difluoro Ketone Peptidomimetics Suggest a Large S1 Pocket for Alzheimer's γ-Secretase: Implications for Inhibitor Design. J. Med. Chem. 2000;43(18):3434–3442. doi: 10.1021/jm000100f. Esler W. P. Das C. Wolfe M. S. … Probing pockets S2–S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimetics. Bioorg. Med. Chem. Lett. 2004;14(8):1935–1938. doi: 10.1016/j.bmcl.2004.01.077. Bolduc D. M. Montagna D. R. Seghers M. C. Wolfe M. S. Selkoe D. J. …

STAT3 pathway in cancers: Past, present, and future.

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms o

MYC inhibitors in multiple myeloma.

The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified. Since then, over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation, especially in hematologic diseases. Indeed, some of the earliest connections among the higher expression of proto-oncogenes (such as MYC), genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma, chronic myeloid leukemia and mouse plasmacytomas. Multiple myeloma (MM), in

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… and other small molecule inhibitors against PPIs Peptidomimetics are small molecules designed to mimic the binding of a peptide sequence to a target [ 149 ] . … For some compounds, we need to report the lack of follow up or publications of recent results in the last years (CX-5461, peptidomimetic inhibitors and other direct MYC inhibitors, such as biologics including peptides and mini-proteins). …

The JAK/STAT signaling pathway: from bench to clinic.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pat

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy.

Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reacti

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… MDM2-Integrins Merlino et al. investigated the effectiveness of peptidomimetic compounds targeting MDM2/X as well as α5β1/αvβ3 integrins. … Peptides and Peptidomimetics in the P53/MDM2/MDM4 Circuitry - a Patent Review . Expert Opin Ther Pat ( 2016 ) 26 : 1417–29 . 10.1080/13543776.2017.1233179 27603098 104 Marine JC Francoz S Maetens M Wahl G Toledo F Lozano G . …

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-7.

Breakthroughs in Medicinal Chemistry [...].

Nanotechnology and Matrix Metalloproteinases in Cancer Diagnosis and Treatment.

Cancer is still one of the leading causes of death worldwide. This great mortality is due to its late diagnosis when the disease is already at advanced stages. Although the efforts made to develop more effective treatments, around 90% of cancer deaths are due to metastasis that confers a systemic character to the disease. Likewise, matrix metalloproteinases (MMPs) are endopeptidases that participate in all the events of the metastatic process. MMPs' augmented concentrations and an increased enzymatic activity have been considered bad prognosis markers of the disease. Therefore, synthetic inhib

PET/CT Imaging for Therapy Assessment in Multieloma, включая MRD.

Фон/цели: Множественная миелома (ММ) представляет собой сложную гематологическую порчу, характеризующуюся аномальным распространением плазменных клеток в костном мозге. [18F]FDG PET/CT стала одним из ключевых способов визуализации, демонстрируя высокую чувствительность и специфичность для обнаружения метаболически активных заболеваний по сравнению с обычными методами визуализации. В настоящем обзоре рассматривается роль изображений ПЕТ/КТ в оценке терапевтической реакции в симптоматической миеломе, включая оценку минимальных остаточных заболеваний (ОРЗ). Методы: Мы изучили литературу, опублико

Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins.

The ability to selectively and directly target activated Ras would provide immense utility for treatment of the numerous cancers that are driven by oncogenic Ras mutations. Patients with disorders driven by overactivated wild-type Ras proteins, such as type 1 neurofibromatosis, might also benefit from progress made in that context. Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes. Inhibition

Molecular Diversity of Lupane Hybrids in Drug Design and Materials Science.

The need for new, more effective drugs to treat cancer, infectious diseases, various parasitic infestations, and metabolic disorders requires innovative approaches to the design of promising molecules. One of these areas is the creation of hybrid structures. Lupane triterpenoids are of significant interest for such research due to their high abundance in natural sources and their renewable nature, their molecular architecture, presence of several easily modifiable functional groups, enantiomeric purity, broad spectrum of biological activity, and low toxicity. Active research into the biologica

Orthogonal targeting of osteoclasts and myeloma cells for radionuclide stimulated dynamic therapy induces multidimensional cell death pathways.

Rationale: Multiple myeloma (MM) is a multifocal malignancy of bone marrow plasma cells, characterized by vicious cycles of remission and relapse that eventually culminate in death. The disease remains mostly incurable largely due to the complex interactions between the bone microenvironment (BME) and MM cells (MMC). In the "vicious cycle" of bone disease, abnormal activation of osteoclasts (OCs) by MMC causes severe osteolysis, promotes immune evasion, and stimulates the growth of MMC. Disrupting these cancer-stroma interactions would enhance treatment response. Methods: To disrupt this cycle

Tumor metastasis to bone.

Establishment of skeletal metastasis involves bidirectional interactions between the tumor cell and the cellular elements in the bone microenvironment. A better understanding of the pathophysiology of bone metastasis will be critical in developing the means to prevent bone metastasis or inhibit its progression. The receptor activator of nuclear factor-kappaB (RANK)/RANK ligand pathway has emerged as the key pathway regulating osteolysis in skeletal metastasis. A number of candidate factors, including the Wnt (wingless int) proteins, endothelin-1, and bone morphogenetic proteins, have been impl

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… The use of RGD-based peptidomimetics (which contain sequence of arginine-glycine-aspartic acid) and MMP inhibitor peptidomimetics in animal models of bone metastasis is associated with smaller size and decreased number of osteolytic lesions [ 76 ]. …

Cyclic Peptides in Modern Drug Discovery: Trends and Therapeutic Directions.

Peptide therapeutics are an important drug modality due to their high specificity, favorable safety, and expanding design potential. Among them, cyclic peptides occupy a space between small molecules and biologics, offering improved rigidity, stability, and target engagement. This report analyzes trends in cyclic peptide research using data from the CAS Content Collection over the past two decades. Results show a steady rise in academic publications and patents, reflecting growing interest across discovery and development. Notably, oral administration is gaining attention, indicating progress

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… In parallel with cyclic peptides, other constrained modalities such as macrocyclic small molecules, miniproteins, and peptidomimetics have also been developed to address challenging biological targets through complementary structural strategies. … Molecular and Chemical Design Backbone Modifications and Noncanonical Residues Chemical modifications such as N -methylation, incorporation of d -amino acids, β-amino acids, and peptidomimetic linkers (e.g., azapeptides, amide isosteres) reduce hydrogen bond donors and proteolytic susceptibility, enhancing …

Emerging Approaches for the Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN): Therapeutic Potential of the C5a/C5aR Axis.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurologic complication of chemotherapy, resulting in symptoms like pain, sensory loss, and numbness in the hands and feet that cause lots of uneasiness in patients with cancer. They often suffer from pain so severe that it interrupts the treatment, thus invalidating the entire chemotherapy-based healing process, and significantly reducing their quality of life. In this paper, we underline the role of the complement system in CIPN, highlighting the relevance of the C5a fragment and its receptor C5aR1, whose activation is thou

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… It is due to the selective impact of modulators only on some of the intracellular transduction pathways that leaves others unaltered, without preventing the binding of the natural ligand to its receptor, in contrast with the classical mechanism of action of orthosteric inhibitors such as peptidomimetics … The cyclic hexapeptide PMX-53, also named 3D53, is a cyclic peptidomimetic C5aR antagonist, with nanomolar affinity towards the effector site with a well-clarified binding mode to the receptor [ 170 ]. …

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing.

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the 'guardian of the genome' and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni syndrome (LFS), the inherited cance

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… The most advanced examples of such approach are stapled peptides, α-helical p53 stapled peptidomimetics among which the ALRN-6924 peptide is the only one in early phase clinical development [ 66 ]. … Targeting protein-protein interactions with small molecules or peptidomimetics (orange, crossed circles) stabilizes p53 and p73 and restores their transcription function (orange arrow). This, in turn, promotes tumor eradication through multiple mechanisms, as depicted in the scheme. …

Molecular Inhibitors of Growth Signals

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Myeloma Bone Disease: A Comprehensive Review.

Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patien

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… Recombinant OPG constructs, soluble RANK, OPG peptidomimetics [ 54 , 55 ], and, more recently, anti-RANKL antibodies such as denosumab have been developed to modulate the RANKL–OPG axis and reduce osteoclastic activity and myeloma [ 56 , 57 , 58 ]. … An Osteoprotegerin-like Peptidomimetic Inhibits Osteoclastic Bone Resorption and Osteolytic Bone Disease in Myeloma Cancer Res. 2007 67 202 208 10.1158/0008-5472.CAN-06-1287 17210700 55. Body J.-J. Greipp P. Coleman R.E. Facon T. Geurs F. Fermand J.-P. Harousseau J.-L. Lipton A. Mariette X. …