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

  • Science. 2021 Mar 26;371(6536):1374-1378. doi: 10.1126/science.abf1611.
Jingxin Qiao  #  1 ,  Yue-Shan Li  #  1 ,  Rui Zeng  #  1 ,  Feng-Liang Liu  #  2  3 ,  Rong-Hua Luo  #  2  3 ,  Chong Huang  #  1 ,  Yi-Fei Wang  #  4 ,  Jie Zhang  1 ,  Baoxue Quan  1 ,  Chenjian Shen  1 ,  Xin Mao  1 ,  Xinlei Liu  1 ,  Weining Sun  1 ,  Wei Yang  1 ,  Xincheng Ni  1 ,  Kai Wang  1 ,  Ling Xu  2  3 ,  Zi-Lei Duan  2  3 ,  Qing-Cui Zou  3 ,  Hai-Lin Zhang  3  5 ,  Wang Qu  3 ,  Yang-Hao-Peng Long  3 ,  Ming-Hua Li  3 ,  Rui-Cheng Yang  1 ,  Xiaolong Liu  1 ,  Jing You  1 ,  Yangli Zhou  1 ,  Rui Yao  1 ,  Wen-Pei Li  1 ,  Jing-Ming Liu  1 ,  Pei Chen  4 ,  Yang Liu  1 ,  Gui-Feng Lin  1 ,  Xin Yang  1 ,  Jun Zou  1 ,  Linli Li  4 ,  Yiguo Hu  1 ,  Guang-Wen Lu  1 ,  Wei-Min Li  1 ,  Yu-Quan Wei  1 ,  Yong-Tang Zheng  6  3 ,  Jian Lei  7  8 ,  Shengyong Yang  7
Affiliations
  • 1. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
  • 3. Kunming National High-level Biosafety Research Center for Non-human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650107, China.
  • 4. Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 5. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
  • 6. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China. [email protected] [email protected] [email protected].
  • 7. State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. [email protected] [email protected] [email protected].
  • 8. National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • # Contributed equally.
PMID: 33602867 DOI: 10.1126/science.abf1611
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.

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