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

被引：1132

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：

CORONAVIRUS; 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

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