Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease

Haixia Su, Sheng Yao, Wenfeng Zhao, Yumin Zhang, Jia Liu, Qiang Shao, Qingxing Wang, Minjun Li, Hang Xie, Weijuan Shang, Changqiang Ke, Lu Feng, Xiangrui Jiang, Jingshan Shen, Gengfu Xiao, Hualiang Jiang, Leike Zhang (), Yang Ye () and Yechun Xu ()
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Haixia Su: Chinese Academy of Sciences
Sheng Yao: University of Chinese Academy of Sciences
Wenfeng Zhao: Chinese Academy of Sciences
Yumin Zhang: Chinese Academy of Sciences
Jia Liu: University of Chinese Academy of Sciences
Qiang Shao: Chinese Academy of Sciences
Qingxing Wang: University of Chinese Academy of Sciences
Minjun Li: Chinese Academy of Sciences
Hang Xie: Chinese Academy of Sciences
Weijuan Shang: Chinese Academy of Sciences
Changqiang Ke: Chinese Academy of Sciences
Lu Feng: Chinese Academy of Sciences
Xiangrui Jiang: Chinese Academy of Sciences
Jingshan Shen: Chinese Academy of Sciences
Gengfu Xiao: University of Chinese Academy of Sciences
Hualiang Jiang: Chinese Academy of Sciences
Leike Zhang: University of Chinese Academy of Sciences
Yang Ye: University of Chinese Academy of Sciences
Yechun Xu: Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

Date: 2021
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DOI: 10.1038/s41467-021-23751-3

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