共 50 条
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
来源:
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.
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页码:1374 / +
页数:89
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