1. Discovery of M Protease Inhibitors Encoded by SARS-CoV-2.
- Author
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Hung HC, Ke YY, Huang SY, Huang PN, Kung YA, Chang TY, Yen KJ, Peng TT, Chang SE, Huang CT, Tsai YR, Wu SH, Lee SJ, Lin JH, Liu BS, Sung WC, Shih SR, Chen CT, and Hsu JT
- Subjects
- Amino Acid Motifs, Animals, Antiviral Agents pharmacology, Betacoronavirus pathogenicity, Catalytic Domain, Chlorocebus aethiops, Coronavirus 3C Proteases, Cysteine Endopeptidases genetics, Cysteine Endopeptidases metabolism, Gene Expression, Molecular Docking Simulation, Protease Inhibitors pharmacology, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Pyrrolidines pharmacology, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, SARS-CoV-2, Sulfonic Acids, Thermodynamics, Vero Cells, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemistry, Betacoronavirus drug effects, Cysteine Endopeptidases chemistry, Protease Inhibitors chemistry, Pyrrolidines chemistry, Viral Nonstructural Proteins chemistry
- 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 (M
pro , 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 recommended., (Copyright © 2020 Hung et al.)- Published
- 2020
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