Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, Yinkai Duan, Jing Yu, Lin Wang, Kailin Yang, Fengjiang Liu, Rendi Jiang, Xinglou Yang, Tian You, Xiaoce Liu, Xiuna Yang, Fang Bai, Hong Liu, Xiang Liu, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Chengfeng Qin, Zhengli Shi, Hualiang Jiang (), Zihe Rao () and Haitao Yang ()
Additional contact information
Zhenming Jin: ShanghaiTech University
Xiaoyu Du: Tsinghua University
Yechun Xu: Chinese Academy of Sciences
Yongqiang Deng: Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences
Meiqin Liu: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Yao Zhao: ShanghaiTech University
Bing Zhang: ShanghaiTech University
Xiaofeng Li: Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences
Leike Zhang: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Chao Peng: Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science
Yinkai Duan: ShanghaiTech University
Jing Yu: ShanghaiTech University
Lin Wang: ShanghaiTech University
Kailin Yang: Cleveland Clinic
Fengjiang Liu: ShanghaiTech University
Rendi Jiang: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Xinglou Yang: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Tian You: ShanghaiTech University
Xiaoce Liu: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Fang Bai: ShanghaiTech University
Hong Liu: Chinese Academy of Sciences
Xiang Liu: Nankai University
Luke W. Guddat: the University of Queensland
Wenqing Xu: ShanghaiTech University
Gengfu Xiao: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Chengfeng Qin: Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences
Zhengli Shi: Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences
Hualiang Jiang: ShanghaiTech University
Zihe Rao: ShanghaiTech University
Haitao Yang: ShanghaiTech University

Nature, 2020, vol. 582, issue 7811, 289-293

Abstract: Abstract A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1–4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds—including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds—as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.

Date: 2020
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DOI: 10.1038/s41586-020-2223-y

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