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

被引:324
|
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
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
收藏
页码:1374 / +
页数:89
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