| Literature DB >> 33602867 |
Jingxin Qiao1, Yue-Shan Li1, Rui Zeng1, Feng-Liang Liu2,3, Rong-Hua Luo2,3, Chong Huang1, Yi-Fei Wang4, Jie Zhang1, Baoxue Quan1, Chenjian Shen1, Xin Mao1, Xinlei Liu1, Weining Sun1, Wei Yang1, Xincheng Ni1, Kai Wang1, Ling Xu2,3, Zi-Lei Duan2,3, Qing-Cui Zou3, Hai-Lin Zhang3,5, Wang Qu3, Yang-Hao-Peng Long3, Ming-Hua Li3, Rui-Cheng Yang1, Xiaolong Liu1, Jing You1, Yangli Zhou1, Rui Yao1, Wen-Pei Li1, Jing-Ming Liu1, Pei Chen4, Yang Liu1, Gui-Feng Lin1, Xin Yang1, Jun Zou1, Linli Li4, Yiguo Hu1, Guang-Wen Lu1, Wei-Min Li1, Yu-Quan Wei1, Yong-Tang Zheng6,3, Jian Lei7,8, Shengyong Yang7.
Abstract
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 (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. 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 with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.Entities:
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Year: 2021 PMID： 33602867 DOI： 10.1126/science.abf1611
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728