PT  - JOURNAL ARTICLE
AU  - Haixia Su
AU  - Sheng Yao
AU  - Wenfeng Zhao
AU  - Minjun Li
AU  - Jia Liu
AU  - WeiJuan Shang
AU  - Hang Xie
AU  - Changqiang Ke
AU  - Meina Gao
AU  - Kunqian Yu
AU  - Hong Liu
AU  - Jingshan Shen
AU  - Wei Tang
AU  - Leike Zhang
AU  - Jianping Zuo
AU  - Hualiang Jiang
AU  - Fang Bai
AU  - Yan Wu
AU  - Yang Ye
AU  - Yechun Xu
TI  - Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease <em>in vitro</em>
AID  - 10.1101/2020.04.13.038687
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.13.038687
4099  - http://biorxiv.org/content/early/2020/04/14/2020.04.13.038687.short
4100  - http://biorxiv.org/content/early/2020/04/14/2020.04.13.038687.full
AB  - Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.Competing Interest StatementThe authors have declared no competing interest.