SARS-CoV-2 M-pro inhibitors with antiviral activity in a transgenic mouse model

被引：326

作者：

Qiao, Jingxin ^{[1
]}

Li, Yue-Shan ^{[1
]}

Zeng, Rui ^{[1
]}

Liu, Feng-Liang ^{[2
,3
]}

Luo, Rong-Hua ^{[2
,3
]}

Huang, Chong ^{[1
]}

Wang, Yi-Fei ^{[4
]}

Zhang, Jie ^{[1
]}

Quan, Baoxue ^{[1
]}

Shen, Chenjian ^{[1
]}

Mao, Xin ^{[1
]}

Liu, Xinlei ^{[1
]}

Sun, Weining ^{[1
]}

Yang, Wei ^{[1
]}

Ni, Xincheng ^{[1
]}

Wang, Kai ^{[1
]}

Xu, Ling ^{[2
,3
]}

Duan, Zi-Lei ^{[2
,3
]}

Zou, Qing-Cui ^{[3
]}

Zhang, Hai-Lin ^{[3
,5
]}

Qu, Wang ^{[3
]}

Long, Yang-Hao-Peng ^{[3
]}

Li, Ming-Hua ^{[3
]}

Yang, Rui-Cheng ^{[1
]}

Liu, Xiaolong ^{[1
]}

You, Jing ^{[1
]}

Zhou, Yangli ^{[1
]}

Yao, Rui ^{[1
]}

Li, Wen-Pei ^{[1
]}

Liu, Jing-Ming ^{[1
]}

Chen, Pei ^{[4
]}

Liu, Yang ^{[1
]}

Lin, Gui-Feng ^{[1
]}

Yang, Xin ^{[1
]}

Zou, Jun ^{[1
]}

Li, Linli ^{[4
]}

Hu, Yiguo ^{[1
]}

Lu, Guang-Wen ^{[1
]}

Li, Wei-Min ^{[1
]}

Wei, Yu-Quan ^{[1
]}

Zheng, Yong-Tang ^{[2
,3
]}

Lei, Jian ^{[1
,6
]}

Yang, Shengyong ^{[1
]}

机构：

[1] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China

[2] Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Kunming Inst Zool, Kunming 650223, Yunnan, Peoples R China

[3] Chinese Acad Sci, Ctr Biosafety Megasci, Kunming Inst Zool, Kunming Natl High Level Biosafety Res Ctr Nonhuma, Kunming 650107, Yunnan, Peoples R China

[4] Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Minist Educ, Chengdu 610041, Sichuan, Peoples R China

[5] Chinese Acad Sci, Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming 650223, Yunnan, Peoples R China

[6] Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Chengdu 610041, Sichuan, Peoples R China

来源：

SCIENCE | 2021年 / 371卷 / 6536期

基金：

国家重点研发计划; 中国国家自然科学基金;

关键词：

3CL PROTEASE INHIBITORS; SARS; DISCOVERY; DESIGN;

D O I：

10.1126/science.abf1611

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：

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (M-pro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing M-pro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 M-pro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of M-pro in complex with MI-23, one of themost potent compounds, revealed its interactionmode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment withMI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

引用

页码：1374 / +

页数：89

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