Advances in the Search for SARS-CoV-2 Mpro and PLpro Inhibitors DOI Creative Commons
Marcel Arruda Diogo,

Augusto Gomes Teixeira Cabral,

Renata Barbosa de Oliveira

et al.

Pathogens, Journal Year: 2024, Volume and Issue: 13(10), P. 825 - 825

Published: Sept. 24, 2024

SARS-CoV-2 is a spherical, positive-sense, single-stranded RNA virus with large genome, responsible for encoding both structural proteins, vital the viral particle’s architecture, and non-structural critical virus’s replication cycle. Among two cysteine proteases emerge as promising molecular targets design of new antiviral compounds. The main protease (Mpro) homodimeric enzyme that plays pivotal role in formation replication–transcription complex, associated papain-like (PLpro), modulates host immune signaling by reversing post-translational modifications ubiquitin interferon-stimulated gene 15 (ISG15) cells. Due to importance these development novel anti-SARS-CoV-2 drugs, purpose this review address aspects related structure, mechanism action strategies inhibitors capable targeting Mpro PLpro. Examples covalent non-covalent are currently being evaluated preclinical clinical studies or already approved therapy will be also discussed show advances medicinal chemistry search molecules treat COVID-19.

Language: Английский

Inhibitors of SARS-CoV-2 PLpro DOI Creative Commons
Dale J. Calleja, Guillaume Lessène, David Komander

et al.

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 10

Published: April 26, 2022

The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers hospitalized patients. antiviral treatments hence remains top priority preventing hospitalization death patients, eventually bringing an end pandemic. proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus nsp3, that harbours papain-like protease (PLpro) domain responsible for cleaving viral polyprotein as part processing. Moreover, nsp3/PLpro also cleaves ubiquitin ISG15 modifications host cell, derailing innate immune responses. Small molecule inhibition PLpro significantly reduces loads infection models, suggesting is excellent drug target next generation antivirals. In this review we discuss conserved structure function ongoing efforts design small inhibitors exploit knowledge. first many repurposing attempts, concluding it unlikely PLpro-targeting drugs already exist. wealth structural information inhibition, which there are now ∼30 distinct crystal structures bound surprising number crystallographic settings. optimisation compound class, based SARS-CoV inhibitor GRL-0617, recapitulate new GRL-0617 derivatives different features PLpro, overcome some liabilities.

Language: Английский

Citations

67
Targeting SARS-CoV-2 papain-like protease in the postvaccine era DOI Open Access
Anh‐Tien Ton, Mohit Pandey, Jason R. Smith

et al.

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

Published: Aug. 24, 2022

Language: Английский

Citations

39
Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19 DOI Open Access
Fatema Hersi,

Anusha Sebastian,

Hamadeh Tarazi

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 254, P. 115380 - 115380

Published: April 17, 2023

Language: Английский

Citations

17
Systematic Exploration of SARS-CoV-2 Adaptation to Vero E6, Vero E6/TMPRSS2, and Calu-3 Cells DOI Creative Commons
Pakorn Aiewsakun, Worakorn Phumiphanjarphak, Natali Ludowyke

et al.

Genome Biology and Evolution, Journal Year: 2023, Volume and Issue: 15(4)

Published: Feb. 28, 2023

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, and scientists around the world are currently studying virus intensively in order fight against on-going pandemic of virus. To do so, SARS-CoV-2 is typically grown lab generate viral stocks for various kinds experimental investigations. However, accumulating evidence suggests that such viruses often undergo cell culture adaptation. Here, we systematically explored adaptation two variants, namely B.1.36.16 variant AY.30 variant, a sub lineage B.1.617.2 (Delta) propagated three different lines, including Vero E6, E6/TMPRSS2, Calu-3 cells. Our analyses detected numerous potential changes scattering across entire genome, many which could be found naturally circulating isolates. Notable ones included mutations spike glycoprotein's multibasic cleavage site, Omicron-defining H655Y mutation on glycoprotein, as well nucleocapsid protein's linker region, all were E6-specific. also identified deletion non-structural protein 1 membrane glycoprotein Calu-3-specific changes. S848C 3, located papain-like protease domain, was change, lines. results highlight high adaptability, emphasize need deep-sequence cultured samples when used intricate sensitive biological experiments, illustrate power evolutionary study shedding lights landscape.

Language: Английский

Citations

13
Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential DOI Open Access
Mohammed Salah Ayoup,

Mariam M. ElShafey,

Hamida Abdel‐Hamid

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 252, P. 115272 - 115272

Published: March 13, 2023

Language: Английский

Citations

13
Structure-based design of SARS-CoV-2 papain-like protease inhibitors DOI Creative Commons
Prakash D. Jadhav, Bo Huang,

J. Osipiuk

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 264, P. 116011 - 116011

Published: Dec. 5, 2023

Language: Английский

Citations

13
Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle DOI Open Access

Mingzhenlong Deng,

Chuang Zhang, Wanli Yan

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2850 - 2850

Published: March 1, 2024

Since the appearance of SARS-CoV-2 in 2019, ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts curb its spread development. The latest studies identified five viral proteins, spike protein (Spike), main protease (3CLpro), papain-like (PLpro), RNA-dependent RNA polymerase (RdRp), helicase (Helicase), which play crucial roles invasion into body lifecycle. development novel anti-SARS-CoV-2 drugs targeting these proteins holds immense promise. Therefore, efficient, high-throughput screening methodologies specifically designed for is utmost importance. Currently, plethora techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate foundational principles underpinning approaches directed at pivotal targets, hoping guide researchers judicious selection refinement strategies, thereby facilitating discovery lead compounds pharmaceuticals.

Language: Английский

Citations

4
Review of the Crystallized Structures of the SARS-CoV-2 papain-like protease DOI
Yue Qiu,

Jiang Hua-Juan,

Yang Yu-Shun

et al.

Journal of Molecular Structure, Journal Year: 2025, Volume and Issue: unknown, P. 141730 - 141730

Published: Feb. 1, 2025

Language: Английский

Citations

0
Molecular docking and dynamics simulation study of medicinal fungi derived secondary metabolites as potential inhibitor for COVID-19 treatment DOI Creative Commons
Md Abu Sayem Khan,

Md Ibrahim Miah,

Zahidul Islam

et al.

Informatics in Medicine Unlocked, Journal Year: 2023, Volume and Issue: 41, P. 101305 - 101305

Published: Jan. 1, 2023

The severity of COVID-19, lack specific treatment, and controversies on the vaccine's efficacy demand development new drugs against SARS-CoV-2. Fungi produce various metabolites with diverse molecular structures that have emerged as promising antiviral drug candidates. Therefore, present study aimed to investigate medicinal fungi derived secondary potential inhibitors 3 different targets associated viral entry (human TMPRSS2) replication (main papain-like protease) through docking dynamic simulation studies. Based our findings, we identified Phelligridin E, Lepiotaprocerine G, Inoscavin A blockers SARS-CoV-2 main protease, human TMPRSS2, respectively. These compounds strongly interacted their corresponding target, passed Lipinski Rule's had acceptable ADMET properties. Drug-protein complexes showed good stability during MD simulation. Estimation binding free energy using MM-GBSA method validated inhibitor compounds. Taken together, believe further in vitro vivo investigations proposed molecules may contribute expanding therapeutic arsenal fight COVID-19.

Language: Английский

Citations

9
Repurposing naproxen as a potential nucleocapsid antagonist of beta-coronaviruses: targeting a conserved protein in the search for a broad-spectrum treatment option DOI
Reza Valadan, Reza Alizadeh‐Navaei, Milad Lagzian

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 26, 2024

Ongoing mutations in the coronavirus family, especially beta-coronaviruses, raise new concerns about possibility of unexpected outbreaks. Therefore, it is crucial to explore alternative treatments reduce impact potential future strains until vaccines can be developed. A promising approach combat virus target its conserved parts such as nucleocapsid, via repurposing existing drugs. The this explored here find a anti-nucleocapsid compound these viruses. 3D models N- and C-terminal domains (CTDs) nucleocapsid consensus sequence were constructed. Each domain was then screened against an FDA-approved drug database, most candidate selected for further analysis. 100 ns molecular dynamics (MD) simulation conducted analyze final more detail. Naproxen found interact with N-terminal salt bridges hydrogen bonds which are completely among all Coronaviridae members. MD analysis also revealed that relevant coordinates naproxen N terminal kept during time. This study provides insights into specific interaction RNA binding pocket could interfere packaging viral genome capsid assembly. Additionally, in-vitro assay demonstrated direct between recombinant protein, supporting computational predictions.

Language: Английский

Citations

3