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

Qiao, Jingxin; Li, Yue-Shan; Zeng, Rui; Liu, Feng-Liang; Luo, Rong-Hua; Huang, Chong; Wang, Yi-Fei; Zhang, Jie; Quan, Baoxue; Shen, Chenjian; Mao, Xin; Liu, Xinlei; Sun, Weining; Yang, Wei; Ni, Xincheng; Wang, Kai; Xu, Ling; Duan, Zi-Lei; Zou, Qing-Cui; Zhang, Hai-Lin; Qu, Wang; Long, Yang-Hao-Peng; Li, Ming-Hua; Yang, Rui-Cheng; Liu, Xiaolong; You, Jing; Zhou, Yangli; Yao, Rui; Li, Wen-Pei; Liu, Jing-Ming; Chen, Pei; Liu, Yang; Lin, Gui-Feng; Yang, Xin; Zou, Jun; Li, Linli; Hu, Yiguo; Lu, Guang-Wen; Li, Wei-Min; Wei, Yu-Quan; Zheng, Yong-Tang; Lei, Jian; Yang, Shengyong

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 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.