Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

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Small molecules in the treatment of COVID-19

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

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Potent and selective covalent inhibition of the papain-like protease from SARS-CoV-2

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 28, 2023

Abstract Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein proteins. As a result, promising target inhibition small-molecule therapeutics. Here we design series covalent inhibitors introducing peptidomimetic linker reactive electrophile onto analogs noncovalent inhibitor GRL0617. most potent compound inhibits with k inact /K I = 9,600 M −1 s , achieves sub-μM EC 50 values against three variants in mammalian cell lines, does not inhibit panel human deubiquitinases (DUBs) at >30 μM concentrations inhibitor. An X-ray co-crystal structure bound validates our strategy establishes molecular basis selectivity structurally similar DUBs. These findings present an opportunity further development inhibitors.

Language: Английский

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Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

Science, Journal Year: 2024, Volume and Issue: 383(6690), P. 1434 - 1440

Published: March 28, 2024

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. papain-like protease (PL pro ) is a promising but challenging drug target. We designed synthesized 85 noncovalent PL inhibitors that bind to recently discovered ubiquitin binding site the known BL2 groove pocket near S4 subsite. Leads inhibited with inhibitory constant K i values from 13.2 88.2 nanomolar. co-crystal structures eight leads revealed their interaction modes. in vivo lead Jun12682 its variants, including nirmatrelvir-resistant strains EC 50 0.44 2.02 micromolar. Oral treatment improved survival reduced lung viral loads lesions infection mouse model, suggesting are antiviral candidates.

Language: Английский

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COVID‐19 in early 2023: Structure, replication mechanism, variants of SARS‐CoV‐2, diagnostic tests, and vaccine & drug development studies

MedComm, Journal Year: 2023, Volume and Issue: 4(2)

Published: April 1, 2023

Coronavirus Disease-19 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome-coronaviruses-2 (SARS-CoV-2), a highly pathogenic and transmissible coronavirus. Most cases of COVID-19 have mild to moderate symptoms, including cough, fever, myalgias, headache. On the other hand, this coronavirus can lead complications death in some cases. Therefore, vaccination most effective tool prevent eradicate disease. Also, rapid diagnostic tests are critical identifying COVID-19. The pandemic has dynamic structure on agenda contains up-to-date developments. This article comprehensively discussed situation since it first appeared. For time, not only structure, replication mechanism, variants SARS-CoV-2 (Alpha, Beta, Gamma, Omicron, Delta, Epsilon, Kappa, Mu, Eta, Zeta, Theta, lota, Lambda) but also all details pandemic, such as how came out, spread, current cases, what precautions should be taken, prevention strategies, vaccines produced, developed, drugs used reviewed every aspect. Herein, comparison for terms procedure, accuracy, cost, time been presented. safety, efficacy, effectiveness against evaluated. Drug studies, therapeutic targets, various immunomodulators, antiviral molecules applied patients with reviewed.

Language: Английский

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COVID-19 therapeutics: Small-molecule drug development targeting SARS-CoV-2 main protease

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(6), P. 103579 - 103579

Published: April 5, 2023

Language: Английский

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SARS‐CoV‐2 Papain‐Like Protease: Structure, Function and Inhibition

ChemBioChem, Journal Year: 2022, Volume and Issue: 23(19)

Published: Aug. 22, 2022

Abstract Emerging variants of SARS‐CoV‐2 and potential novel epidemic coronaviruses underline the importance investigating various viral proteins as drug targets. The papain‐like protease has been less explored than other proteins; however, its substantive role in replication impact on host immune response make it a suitable target to study. This review article focuses structure function (PL pro ) SARS‐CoV‐2, including concern, compares those coronaviruses, such SARS‐CoV‐1 MERS‐CoV. protease's recognition motif is mirrored ubiquitin ISG15, which are involved antiviral response. Inhibitors, GRL0617 derivatives, their prospects future agents also discussed.

Language: Английский

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Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents

Drug Design Development and Therapy, Journal Year: 2022, Volume and Issue: Volume 16, P. 2463 - 2478

Published: Aug. 1, 2022

Abstract: The current pandemic caused by the COVID-19 disease has reached everywhere in world and affected every aspect of our lives. As data, World Health Organization (WHO) reported more than 300 million confirmed cases worldwide 5 deaths. M pro is an enzyme that plays a key role life cycle SARS-CoV-2 virus, it vital for progression. seems to have several allosteric sites can hinder catalytic activity. Furthermore, some these are located at or nearby dimerization interface which essential overall In this review paper, we investigate potential site act as drug target, especially since they interestingly appear be resistant mutation. work illustrated through three subsequent sections: First, two main categories been explained discussed. Second, total six pockets studied evaluated their druggability cavity characteristics. Third, experimental computational attempts discovery new inhibitors To sum up, paper gives detailed insight into feasibility developing treatment disease. Graphical Keywords: COVID-19, , SARS-CoV-2, sites, druggability, antiviral

Language: Английский

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Targeting SARS-CoV-2 papain-like protease in the postvaccine era

Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(11), P. 906 - 919

Published: Aug. 24, 2022

Language: Английский

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Green and efficient one-pot three-component synthesis of novel drug-like furo[2,3-d]pyrimidines as potential active site inhibitors and putative allosteric hotspots modulators of both SARS-CoV-2 MPro and PLPro

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 135, P. 106390 - 106390

Published: Jan. 28, 2023

Language: Английский

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