RT Journal Article SR Electronic T1 Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.13.038687 DO 10.1101/2020.04.13.038687 A1 Haixia Su A1 Sheng Yao A1 Wenfeng Zhao A1 Minjun Li A1 Jia Liu A1 WeiJuan Shang A1 Hang Xie A1 Changqiang Ke A1 Meina Gao A1 Kunqian Yu A1 Hong Liu A1 Jingshan Shen A1 Wei Tang A1 Leike Zhang A1 Jianping Zuo A1 Hualiang Jiang A1 Fang Bai A1 Yan Wu A1 Yang Ye A1 Yechun Xu YR 2020 UL http://biorxiv.org/content/early/2020/04/14/2020.04.13.038687.abstract 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.