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A review of potential suggested drugs for coronavirus disease (COVID-19) treatment.

The latest pandemic, coronavirus disease-2019 (COVID-19), is associated with high prevalence and easy transmission, which is expanding globally with no conventional treatment or vaccine. The new virus revealed 79% and 50% genomic similarities with severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), respectively. Accordingly, since the disease resists testing and adopting new therapeutics, repositioning pre-existing drugs may present a fast and attractive strategy with known safety, characteristics, and dosage used. However, they

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… Moreover, the main protease or chymotrypsin-like protease of COVID-19 has been suggested as a potential drug target ( Kaldor et al., 1997 ; Xu et al., 2020b ; Yamamoto et al., 2004 ). …

The Role of the Ubiquitin System in Eye Diseases.

The ubiquitin-proteasome system (UPS) is a fundamental process that regulates various biological functions, including immune response, cell cycle, oxidative stress, migration, and cellular proliferation. This system is responsible for the degradation of proteins, while proteasomes play a significant role in mechanisms involved in health and human diseases. The participation of the UPS in immune response is particularly relevant, leading to the involvement of immunoproteasomes. This specialized proteasome is involved in the processing and presentation of antigenic peptides, making it crucial fo

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… The inner β rings exhibit the following distinct catalytic activities: post-glutamyl (β1) activity, which resembles that of caspases and cleaves substrates at acidic residues; trypsin-like (β2) activity, which targets basic residues; and chymotrypsin-like (β5) activity, which cleaves hydrophobic residues …

Exploring the Therapeutic Potential of Ganoderma lucidum in Cancer.

Triterpenoids, such as ganoderic acid, and polysaccharides, including β-D-glucans, α-D-glucans, and α-D-mannans, are the main secondary metabolites of the medicinal fungus Ganoderma lucidum. There is evidence of the effects of ganoderic acid in hematological malignancies, whose mechanisms involve the stimulation of immune response, the macrophage-like differentiation, the activation of MAP-K pathway, an IL3-dependent cytotoxic action, the induction of cytoprotective autophagy, and the induction of apoptosis. In fact, this compound has been tested in twenty-six different human cancer cell types

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… Several enzymes have also been isolated from G. lucidum , such as cellulase, carboxyproteinase, amylase, endopectin methyltranseliminase, endopolygalacturonase, manganese superoxide dismutase, endo- and exo-polygalacturonase, isoforms of chymotrypsin inhibitors, and laccase isoenzymes [ 17 ]. …

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboran

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… Inhibition of the serine proteases leukocyte elastase, pancreatic elastase, cathepsin G, and chymotrypsin by peptide boronic acids. J. Biol. Chem. 1984;259:15106–15114. doi: 10.1016/S0021-9258(17)42521-X. 112. …

Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial.

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an ada

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… The action mechanism of bortezomib is the reversible inhibition of the chymotrypsin-like activity of the 20S proteasome core in the 26S proteasome complex, which degrades ubiquitinated proteins that regulate the intracellular concentration of unneeded or damaged proteins. …

Recent advances in the management of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease presenting highly heterogeneous clinical manifestations and multi-systemic involvement. Patients are susceptible to relapse- and remission, thus making management challenging. Moreover, a considerable number of side effects may occur with conventional therapies; therefore, there is clearly a need for new therapeutic strategies. Since the pathogenesis of SLE is highly complex, it is far from being fully understood. However, greater understanding of the pathways and of the cellular and molecular mediators involved in SLE is being

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… Bortezomib reversibly binds to the 26S proteasome and inhibits its chymotrypsin-like activity, resulting in plasma cell depletion 81 . Recently, Alexander et al . 82 investigated the safety and efficacy of bortezomib in 12 patients with refractory SLE. …

Sestrin-2: a new biomarker for type 2 Diabetes Mellitus and Insulin resistance.

Multiple myeloma (MM) is the second most common haematological malignancy characterised by clonal proliferation of plasma cells within the bone marrow. Despite advances in treatment options, myeloma remains incurable. Relapsed MM poses significant challenges due to clonal evolution, drug resistance, patient comorbidities and therefore complexities of therapeutic decision-making. A critical question in managing relapsed MM is whether to switch drug classes or retreat with agents within the same class. The question is present with the recent addition of three new drug classes (XPO1 inhibitors, B

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… The 26 S proteasome, composed of a 19 S regulatory particle and a 20 S catalytic core, contains three catalytic subunits—β1, β2, and β5—responsible for caspase-, trypsin-, and chymotrypsin-like activities, respectively [ 51 – 53 ]. …

T-Type Calcium Channels: A Mixed Blessing.

The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not complete

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… This reduced toxicity is thought to be due to higher selectivity of CFZ for the chymotrypsin-like activity of the ꞵ5 sub-unit of the 20S core particle of the proteasome [ 68 ]. …

Recent advances in management of COVID-19: A review.

The coronavirus disease 2019 (COVID-19) pandemic caused and is still causing significant mortality and economic consequences all over the globe. As of today, there are three U.S Food and Drug administration (FDA) approved vaccines, Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccine. Also, the antiviral drug remdesivir and two combinations of monoclonal antibodies are authorized for Emergency use (EUA) in certain patients. Furthermore, baricitinib was approved in Japan (April 23, 2021). Despite available vaccines and EUA, pharmacological therapy for the prevention and treatment of COVID-19 i

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… A hypothesis suggests that a high dose of famotidine could produce antiviral effect by inhibiting two COVID-19 proteases, papain-like protease and 3-chymotrypsin-like protease [50] , [54] . Nonetheless, in silico studies did not support this hypothesis. …

Microorganisms Associated with the Marine Sponge Scopalina hapalia: A Reservoir of Bioactive Molecules to Slow Down the Aging Process.

Aging research aims at developing therapies that delay normal aging processes and some related pathologies. Recently, many compounds and extracts from natural products have been shown to slow aging and/or extend lifespan. Marine sponges and their associated microorganisms have been found to produce a wide variety of bioactive secondary metabolites; however, those from the Southwest of the Indian Ocean are much less studied, especially regarding anti-aging activities. In this study, the microbial diversity of the marine sponge Scopalina hapalia was investigated by metagenomic analysis. Twenty-s

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… Elastase is a member of the chymotrypsin family of proteases and is primarily responsible for the degradation of elastin, which is an important protein giving elasticity to arteries, lungs and skin. …

Efficacy of bortezomib as first-line treatment for patients with multiple myeloma.

Recent years have seen a dramatic change in the approach towards diagnosing and treating Multiple Myeloma. Newer and more target specific approach to treatment has prolonged the survival for patients with multiple myeloma. The proteasome inhibitors make an important class of anti-myeloma drugs that disrupts the proteolytic machinery of the tumor cells preferentially, enhancing their susceptibility to apoptosis. Bortezomib, in particular has shown significant clinical efficacy in myeloma treatment. It is the most commonly used proteasome inhibitor and has been tested to be effective in prolongi

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… in cytoplasm and the nucleus. 24 Proteasomes are comprised of complex inner (α1 to α7 subunits) and outer (β1 to β7 subunits) cylindrical structures with three compartments performing catalytic (20S) and regulatory (19S) processes. 25 The 20S subunit core eliminates the ubiquinated proteins via its Chymotrypsin-like …

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors.

The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targetin

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… The 19S subunit cleaves the Ub moiety from the protein substrate and threads the unfolded protein into the catalytic core, where the substrate is degraded via chymotrypsin-like, trypsin-like, and caspase-like proteolysis activities [ 10 , 12 , 13 ]. … cancer, and more | [ 36 , 62 , 63 , 64 ] Oprozomib | Proteasome (20S particle) | Irreversibly binds active sites of 20S proteasome | Phase 1b/2 | MM [ 65 ] | Solid tumors, hepatocellular carcinoma, MM, waldenstrom macroglobulinemia, and more | [ 66 ] Ixazomib | Proteasome (20S particle) | Inhibits chymotrypsin-like …

Engineering TCR-directed T-cells for the treatment of multiple myeloma.

Multiple myeloma (MM) is a virtually incurable plasma cell malignancy characterized by malignant cells that expand within the tumor-permissive bone marrow (BM) microenvironment. Novel strategies are urgently needed to improve the outcomes of patients with difficult-to-treat and therapy-refractory disease. The ability to genetically manipulate T-cells and the introduction of adoptive cellular therapies (ACTs) has improved the treatment of relapsed and/or refractory (RR)MM. Emerging evidence supports the efficacy of ACTs as early lines of cancer treatment, potentially even as an alternative to a

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… Within this structure, expression of processive β1i (caspase-like), β2i (trypsin-like), and β5i (chymotrypsin-like) subunits define immunoproteasomes ( Figure 4 ; 69 – 74 ). …

Hallmarks of ribosomopathies.

Ribosomopathies are diseases caused by defects in ribosomal constituents or in factors with a role in ribosome assembly. Intriguingly, congenital ribosomopathies display a paradoxical transition from early symptoms due to cellular hypo-proliferation to an elevated cancer risk later in life. Another association between ribosome defects and cancer came into view after the recent discovery of somatic mutations in ribosomal proteins and rDNA copy number changes in a variety of tumor types, giving rise to somatic ribosomopathies. Despite these clear connections between ribosome defects and cancer,

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… This altered proteasomal unit expression in RPL10-R98S cells is associated with reduced chymotrypsin-like and caspase-like proteasomal activities, and with elevated sensitivity of RPL10-R98S expressing cells for the clinically used proteasome inhibitors, bortezomib and carfilzomib ( 74 ). …

Current and New Therapeutic Strategies for Relapsed and Refractory Multiple Myeloma: An Update.

Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the

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… Proteasome Inhibitors Carfilzomib is a second-generation proteasome inhibitor that irreversibly and selectively inhibits the chymotrypsin-like site of the proteasome. …

Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives.

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles

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… PSMA3 interacts with PSMA3–AS1 pre-mRNA to form an RNA duplex, leading to increased stability of PSMA3 and thereby promoting Chymotrypsin-Like proteasome activity [ 89 ]. BMME-induced MM drug resistance may be further explained by a vicious cycle existing between MM cells and marrow adipocytes. …

Efficacy and Toxicity Profile of Carfilzomib-Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review.

Carfilzomib (CFZ) is a proteasome inhibitor currently approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Multiple trials are ongoing to evaluate its efficacy and safety in newly diagnosed multiple myeloma (NDMM). The use of CFZ-based two- or three-drug combination regimens as induction for the management of NDMM is an emerging approach. CFZ-based regimens include combinations of immunomodulators, alkylating agents, and monoclonal antibodies along with dexamethasone. In this review, we assess the efficacy and toxicity of CFZ-based regimens in NDMM. We reviewed a tota

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… There are three proteolytic sites available on proteasomes that mediate the degradation of proteins and are named caspase-like ( C-L ), chymotrypsin-like ( ChT-L ), and trypsin-like ( T-L ) sites. …

Advances in Peptidomimetics for Next-Generation Therapeutics: Strategies, Modifications, and Applications.

Over the past two decades, peptide drug discovery has experienced a remarkable renaissance, with organic chemistry and biotechnology emerging as pivotal tools for developing peptidomimetics that exhibit improved stability, specificity, and bioavailability compared to conventional peptides. This review systematically examines methodologies for modifying peptide backbones to achieve targeted properties, highlighting recent advances facilitated by modern biotechnological innovations for novel molecular transformations. Additionally, the review emphasizes the practical applications of peptides and

Curcumin Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far?

Curcumin has been credited with a wide spectrum of pharmacological properties for the prevention and treatment of several chronic diseases such as arthritis, autoimmune diseases, cancer, cardiovascular diseases, diabetes, hemoglobinopathies, hypertension, infectious diseases, inflammation, metabolic syndrome, neurological diseases, obesity, and skin diseases. However, due to its weak solubility and bioavailability, it has limited potential as an oral medication. Numerous factors including low water solubility, poor intestinal permeability, instability at alkaline pH, and fast metabolism contri

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… For instance, supplementation with curcumin/piperine (500 mg-2g/day curcumin plus 5–20 mg/day piperine) formulation resulted in a significant reduction in ubiquitin, muscle atrophy F box (MAFbx)/atrogin-1, chymotrypsin-like protease, interleukin 2 (IL-2), TNF-α, INF, IL-6, IL-10, and enhancement in bioavailability … well-tolerated, no adverse side effects | ( 82 ) curcumin + piperine | healthy volunteers | 8 | single dose | 2 g+20 mg | ↑bioavailability no adverse side effects | safe, well-tolerated, | ( 55 ) recreationally active subjects | 23 | 11 days | 2 g/day +20 mg/day | ↑DOMS time, ↓Ubiquitin, ↓MAFbx/atrogin-1, ↓chymotrypsin-like …

Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond.

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defi

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… An enzyme in mast cells with properties like chymotrypsin. J. Exp. Med. 1959;110:451–460. doi: 10.1084/jem.110.3.451. 42. Benditt E.P., Arase M. Enzyme kinetics in a histochemical system. J. Histochem. Cytochem. 1958;6:431–434. doi: 10.1177/6.6.431. 43. Gomori G. …