Structure of M-pro 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; Haitao Yang

doi:10.1038/s41586-020-2223-y

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Structure of M-pro from SARS-CoV-2 and discovery of its inhibitors

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Structure of M-pro 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, …

Nature (London), Vol.582(7811), p.289

06/01/2020

DOI: 10.1038/s41586-020-2223-y

PMID: 32272481

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Abstract

A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential. 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 (M-pro) of SARS-CoV-2: M-pro 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-2(5,6). We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M-pro 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 M-pro. Six of these compounds inhibited M-pro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 mu M. 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.

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Title: Subtitle: Structure of M-pro from SARS-CoV-2 and discovery of its inhibitors
Creators: Zhenming Jin - ShanghaiTech University
Xiaoyu Du - Tsinghua University
Yechun Xu - Shanghai Institute of Materia Medica
Yongqiang Deng - Acad Mil Med Sci, Beijing Inst Microbiol & Epidemiol, Dept Virol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China
Meiqin Liu - Mega (Czechia)
Yao Zhao - ShanghaiTech University
Bing Zhang - ShanghaiTech University
Xiaofeng Li - Academy of Military Medical Sciences
Leike Zhang - Wuhan Institute of Virology
Chao Peng - Shanghai Advanced Research Institute
Yinkai Duan - ShanghaiTech University
Jing Yu - ShanghaiTech University
Lin Wang - ShanghaiTech University
Kailin Yang - Cleveland Clinic
Fengjiang Liu - ShanghaiTech University
Rendi Jiang - Mega (Czechia)
Xinglou Yang - Mega (Czechia)
Tian You - ShanghaiTech University
Xiaoce Liu - ShanghaiTech University
Xiuna Yang - ShanghaiTech University
Fang Bai - ShanghaiTech University
Hong Liu - Shanghai Institute of Materia Medica
Xiang Liu - Nankai University
Luke W. Guddat - The University of Queensland
Wenqing Xu - Shanghai Advanced Research Institute
Gengfu Xiao - Wuhan Institute of Virology
Chengfeng Qin - Acad Mil Med Sci, Beijing Inst Microbiol & Epidemiol, Dept Virol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China
Zhengli Shi - Mega (Czechia)
Hualiang Jiang - Chinese Academy of Sciences
Zihe Rao - Nankai University
Haitao Yang - ShanghaiTech University
Resource Type: Journal article
Publication Details: Nature (London), Vol.582(7811), p.289
DOI: 10.1038/s41586-020-2223-y
PMID: 32272481
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Publisher: NATURE PORTFOLIO
Number of pages: 17
Grant note: 81520108019 / Project of International Cooperation and Exchanges NSFC 20431900200 / Science and Technology Commission of Shanghai Municipality; Science & Technology Commission of Shanghai Municipality (STCSM) 2020AB40007 / Department of Science and Technology of Guangxi Zhuang Autonomous Region 2017YFC0840300; 2020YFA0707500 / National Key R&D Program of China
Language: English
Date published: 06/01/2020
Academic Unit: Radiation Oncology
Record Identifier: 9984696724702771

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