Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro
Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro
Abstract 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.
Su Haixia、Zhao Wenfeng、Ke Changqiang、Liu Hong、Shen Jingshan、Zuo Jianping、Ye Yang、Xu Yechun、Tang Wei、Bai Fang、Shang WeiJuan、Zhang Leike、Yao Sheng、Yu Kunqian、Liu Jia、Li Minjun、Xie Hang、Gao Meina、Jiang Hualiang、Wu Yan
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences||Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesShanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesShanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesCAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences||Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech UniversityState Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
医药卫生理论药学基础医学
Su Haixia,Zhao Wenfeng,Ke Changqiang,Liu Hong,Shen Jingshan,Zuo Jianping,Ye Yang,Xu Yechun,Tang Wei,Bai Fang,Shang WeiJuan,Zhang Leike,Yao Sheng,Yu Kunqian,Liu Jia,Li Minjun,Xie Hang,Gao Meina,Jiang Hualiang,Wu Yan.Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro[EB/OL].(2025-03-28)[2025-06-14].https://www.biorxiv.org/content/10.1101/2020.04.13.038687.点此复制
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