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Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients

Hai-xia Su1,2, Sheng Yao2,3, Wen-feng Zhao1,4, Min-jun Li5, Jia Liu2,3, Wei-juan Shang6, Hang Xie1, Chang-qiang Ke3, Hang-chen Hu1,2, Mei-na Gao1,2, Kun-qian Yu1,2, Hong Liu2,3, Jing-shan Shen1,2, Wei Tang1,2, Lei-ke Zhang6, Geng-fu Xiao6, Li Ni7, Dao-wen Wang7, Jian-ping Zuo2,3, Hua-liang Jiang1,2,8, Fang Bai8, Yan Wu6, Yang Ye2,3,9, Ye-chun Xu1,2
1 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4 Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
5 Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China
6 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
7 Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
8 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
9 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Correspondence to: Fang Bai: baifang@shanghaitech.edu.cn, Yan Wu: wuyan@wh.iov.cn, Yang Ye: yye@simm.ac.cn, Ye-chun Xu: ycxu@simm.ac.cn,
DOI: 10.1038/s41401-020-0483-6
Received: 9 June 2020
Accepted: 14 July 2020
Advance online: 31 July 2020

Abstract

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic 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 was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively 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 effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.
Keywords: SARS-CoV-2; 3CL protease; traditional Chinese medicines; Shuanghuanglian oral liquid; baicalin; baicalein

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