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

被引：2210

作者：

Jin, Zhenming ^{[1
,2
,3
,4
]}

Du, Xiaoyu ^{[3
,4
]}

Xu, Yechun ^{[5
]}

Deng, Yongqiang ^{[6
]}

Liu, Meiqin ^{[7
]}

Zhao, Yao ^{[1
,2
]}

Zhang, Bing ^{[1
,2
]}

Li, Xiaofeng ^{[6
]}

Zhang, Leike ^{[7
]}

Peng, Chao ^{[8
]}

Duan, Yinkai ^{[1
,2
]}

Yu, Jing ^{[1
,2
]}

Wang, Lin ^{[1
,2
]}

Yang, Kailin ^{[9
]}

Liu, Fengjiang ^{[1
,2
]}

Jiang, Rendi ^{[7
]}

Yang, Xinglou ^{[7
]}

You, Tian ^{[1
,2
]}

Liu, Xiaoce ^{[1
,2
]}

Yang, Xiuna ^{[1
,2
]}

Bai, Fang ^{[1
,2
]}

Liu, Hong ^{[5
]}

Liu, Xiang ^{[10
]}

Guddat, Luke W. ^{[11
]}

Xu, Wenqing ^{[1
,2
,8
]}

Xiao, Gengfu ^{[7
]}

Qin, Chengfeng ^{[6
]}

Shi, Zhengli ^{[7
]}

Jiang, Hualiang ^{[1
,2
,5
]}

Rao, Zihe ^{[1
,2
,3
,4
,10
]}

Yang, Haitao ^{[1
,2
]}

机构：

[1] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China

[2] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China

[3] Tsinghua Univ, Sch Life Sci, Struct Biol Lab, Beijing, Peoples R China

[4] Tsinghua Univ, Sch Med, Beijing, Peoples R China

[5] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai, Peoples R China

[6] Acad Mil Med Sci, Beijing Inst Microbiol & Epidemiol, Dept Virol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China

[7] Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, CAS Key Lab Special Pathogens, Wuhan, Peoples R China

[8] Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai, Peoples R China

[9] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA

[10] Nankai Univ, State Key Lab Med Chem Biol, Frontiers Sci Ctr Cell Response, Coll Life Sci,Coll Pharm, Tianjin, Peoples R China

[11] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia

来源：

NATURE | 2020年 / 582卷 / 7811期

基金：

国家重点研发计划;

关键词：

RESPIRATORY SYNDROME-CORONAVIRUS; VIRUS MAIN PROTEASE; SARS; PROTEINASE; EBSELEN; SPECIFICITIES; PREVENTION; DOCKING; COMPLEX; BINDING;

D O I：

10.1038/s41586-020-2223-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：289 / +

页数：17

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