Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Antimicrobial Agents and Chemotherapy
Hui-Chen HungJohn Tsu-An Hsu

Abstract

The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C-like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the Mpro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC50) of 26.4 ± 1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC50) of 0.91 ± 0.03 μM. Only a small portion of SARS-CoV-2 Mpro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis, indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealed that the recognition and binding groups of GC376 within the active site of SARS-CoV-2 Mpro provide important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is reco...Continue Reading

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Citations

Dec 9, 2020·Biochemical and Biophysical Research Communications·Zhenming JinHaitao Yang
Feb 19, 2021·Frontiers in Pharmacology·Hylemariam Mihiretie MengistTengchuan Jin
Mar 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xi HeDai Wang
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Sep 23, 2021·Journal of Biomolecular Structure & Dynamics·Eldhose IypeMainak Dutta

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Methods Mentioned

BETA
Fluorescence
FRET
X-ray
X ray
fluorescence resonance energy transfer

Software Mentioned

AutoDock Tools
MaxEnt
LigandFit
Waters MassLynx
GraphPad Prism

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