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

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(p...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Reports
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099175/
https://www.ncbi.nlm.nih.gov/pubmed/33602867
http://dx.doi.org/10.1126/science.abf1611
Descripción
Sumario: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.

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