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

文献类型：期刊论文

作者Jin, Zhenming7,8,9,10; Du, Xiaoyu9,10; Xu, Yechun11; Deng, Yongqiang1; Liu, Meiqin2; Zhao, Yao7,8; Zhang, Bing7,8; Li, Xiaofeng1; Zhang, Leike2; Peng, Chao3
刊名NATURE
出版日期2020-04-09
页码24
ISSN号0028-0836
DOI10.1038/s41586-020-2223-y
通讯作者Jiang, Hualiang(hljiang@simm.ac.cn) ; Rao, Zihe(raozh@mail.tsinghua.edu.cn) ; Yang, Haitao(yanght@shanghaitech.edu.cn)
英文摘要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.
WOS关键词RESPIRATORY SYNDROME-CORONAVIRUS ; VIRUS MAIN PROTEASE ; SARS ; PROTEINASE ; EBSELEN ; SPECIFICITIES ; PREVENTION ; DOCKING ; COMPLEX ; BINDING
资助项目National Key R&D Program of China[2017YFC0840300] ; National Key R&D Program of China[2020YFA0707500] ; Project of International Cooperation and Exchanges NSFC[81520108019] ; Science and Technology Commission of Shanghai Municipality[20431900200] ; Department of Science and Technology of Guangxi Zhuang Autonomous Region[2020AB40007]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PUBLISHING GROUP
WOS记录号WOS:000537932300001
源URL[http://119.78.100.183/handle/2S10ELR8/280060]  
专题中国科学院上海药物研究所
通讯作者Jiang, Hualiang; Rao, Zihe; Yang, Haitao
作者单位1.Acad Mil Med Sci, Beijing Inst Microbiol & Epidemiol, Dept Virol, State Key Lab Pathogen & Biosecur, Beijing, Peoples R China
2.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, CAS Key Lab Special Pathogens, Wuhan, Peoples R China
3.Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai, Peoples R China
4.Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA
5.Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld, Australia
6.Nankai Univ, State Key Lab Med Chem Biol, Frontiers Sci Ctr Cell Response, Coll Life Sci,Coll Pharm, Tianjin, Peoples R China
7.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China
8.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
9.Tsinghua Univ, Sch Life Sci, Struct Biol Lab, Beijing, Peoples R China
10.Tsinghua Univ, Sch Med, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Jin, Zhenming,Du, Xiaoyu,Xu, Yechun,et al. Structure of M-pro from SARS-CoV-2 and discovery of its inhibitors[J]. NATURE,2020:24.
APA Jin, Zhenming.,Du, Xiaoyu.,Xu, Yechun.,Deng, Yongqiang.,Liu, Meiqin.,...&Yang, Haitao.(2020).Structure of M-pro from SARS-CoV-2 and discovery of its inhibitors.NATURE,24.
MLA Jin, Zhenming,et al."Structure of M-pro from SARS-CoV-2 and discovery of its inhibitors".NATURE (2020):24.

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来源：上海药物研究所

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