2. Academic Validation
  3. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model

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

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. yangsy@scu.edu.cn leijian@scu.edu.cn zhengyt@mail.kiz.ac.cn.
  • 7 State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. yangsy@scu.edu.cn leijian@scu.edu.cn zhengyt@mail.kiz.ac.cn.
  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-180318
    SARS-CoV 抑制剂
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