Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

被引：1172

作者：

Dai, Wenhao ^{[1
,2
]}

Zhang, Bing ^{[3
,4
]}

Jiang, Xia-Ming ^{[5
]}

Su, Haixia ^{[1
,6
]}

Li, Jian ^{[1
,6
]}

Zhao, Yao ^{[3
,4
]}

Xie, Xiong ^{[1
,6
]}

Jin, Zhenming ^{[3
,4
]}

Peng, Jingjing ^{[1
,6
]}

Liu, Fengjiang ^{[3
,4
]}

Li, Chunpu ^{[1
,6
]}

Li, You ^{[8
]}

Bai, Fang ^{[3
,4
]}

Wang, Haofeng ^{[3
,4
]}

Cheng, Xi ^{[1
]}

Cen, Xiaobo ^{[8
]}

Hu, Shulei ^{[1
]}

Yang, Xiuna ^{[3
,4
]}

Wang, Jiang ^{[1
,6
]}

Liu, Xiang ^{[9
]}

Xiao, Gengfu ^{[5
]}

Jiang, Hualiang ^{[1
,3
,4
,6
]}

Rao, Zihe ^{[3
,4
]}

Zhang, Lei-Ke ^{[5
]}

Xu, Yechun ^{[1
,6
]}

Yang, Haitao ^{[3
,4
]}

Liu, Hong ^{[1
,2
,6
,7
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] China Pharmaceut Univ, Sch Pharm, Nanjing 210009, Jiangsu, Peoples R China

[3] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China

[4] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

[5] Chinese Acad Sci, Ctr Biosafety Mega Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Peoples R China

[6] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[7] Nanjing Univ Chinese Med, Coll Pharm, Nanjing 210023, Peoples R China

[8] Sichuan Univ, Westchina Hosp, Natl Chengdu Ctr Safety Evaluat Drugs, Chengdu 610041, Sichuan, Peoples R China

[9] Nankai Univ, State Key Lab Med Chem Biol, Frontiers Sci Ctr Cell Response, Coll Pharm,Coll Life Sci, Tianjin 300353, Peoples R China

来源：

SCIENCE | 2020年 / 368卷 / 6497期

基金：

中国国家自然科学基金;

关键词：

INHIBITORS; 3C;

D O I：

10.1126/science.abb4489

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：

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M-pro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting M-pro. Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M-pro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of M-pro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

引用

页码：1331 / +

页数：35

共 34 条

[1] PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].

Adams, Paul D. ;

Afonine, Pavel V. ;

Bunkoczi, Gabor ;

Chen, Vincent B. ;

Davis, Ian W. ;

Echols, Nathaniel ;

Headd, Jeffrey J. ;

Hung, Li-Wei ;

Kapral, Gary J. ;

Grosse-Kunstleve, Ralf W. ;

McCoy, Airlie J. ;

Moriarty, Nigel W. ;

Oeffner, Robert ;

Read, Randy J. ;

Richardson, David C. ;

Richardson, Jane S. ;

Terwilliger, Thomas C. ;

Zwart, Peter H. .

ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221

[2] Coronavirus main proteinase (3CLpro) structure:: Basis for design of anti-SARS drugs [J].

Anand, K ;

Ziebuhr, J ;

Wadhwani, P ;

Mesters, JR ;

Hilgenfeld, R .

SCIENCE, 2003, 300 (5626) :1763-1767

[3] Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain [J].

Anand, K ;

Palm, GJ ;

Mesters, JR ;

Siddell, SG ;

Ziebuhr, J ;

Hilgenfeld, R .

EMBO JOURNAL, 2002, 21 (13) :3213-3224

[4]

[Anonymous], 2020, NEW ENGL J MED, DOI DOI 10.1056/NEJMoa2001191

[5] Presumed Asymptomatic Carrier Transmission of COVID-19 [J].

Bai, Yan ;

Yao, Lingsheng ;

Wei, Tao ;

Tian, Fei ;

Jin, Dong-Yan ;

Chen, Lijuan ;

Wang, Meiyun .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2020, 323 (14) :1406-1407

[6]

Brodersen Hanne Torp, 2020, Project Director, Faerchfonden

[7]

Cao B, 2020, NEW ENGL J MED, V382

[8] A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster [J].

Chan, Jasper Fuk-Woo ;

Yuan, Shuofeng ;

Kok, Kin-Hang ;

To, Kelvin Kai-Wang ;

Chu, Hin ;

Yang, Jin ;

Xing, Fanfan ;

Liu, Jieling ;

Yip, Cyril Chik-Yan ;

Poon, Rosana Wing-Shan ;

Tsoi, Hoi-Wah ;

Lo, Simon Kam-Fai ;

Chan, Kwok-Hung ;

Poon, Vincent Kwok-Man ;

Chan, Wan-Mui ;

Ip, Jonathan Daniel ;

Cai, Jian-Piao ;

Cheng, Vincent Chi-Chung ;

Chen, Honglin ;

Hui, Christopher Kim-Ming ;

Yuen, Kwok-Yung .

LANCET, 2020, 395 (10223) :514-523

[9] Emerging coronaviruses: Genome structure, replication, and pathogenesis [J].

Chen, Yu ;

Liu, Qianyun ;

Guo, Deyin .

JOURNAL OF MEDICAL VIROLOGY, 2020, 92 (04) :418-423

[10]

Cohen J., 2020, SCIENCE, DOI 10.1126/science.abb0659

← 1 2 3 4 →