• Antimicrob. Agents Chemother. · Aug 2020

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

    • Hui-Chen Hung, Yi-Yu Ke, Sheng Yu Huang, Peng-Nien Huang, Yu-An Kung, Teng-Yuan Chang, Kuei-Jung Yen, Tzu-Ting Peng, Shao-En Chang, Chin-Ting Huang, Ya-Ru Tsai, Szu-Huei Wu, Shiow-Ju Lee, Jiunn-Horng Lin, Bing-Sin Liu, Wang-Chou Sung, Shin-Ru Shih, Chiung-Tong Chen, and John Tsu-An Hsu.
    • Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
    • Antimicrob. Agents Chemother. 2020 Aug 20; 64 (9).

    AbstractThe 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 recommended.Copyright © 2020 Hung et al.

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