Journal
SCIENCE
Volume 371, Issue 6536, Pages 1374-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abf1611
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Funding
- fast-track research fund on COVID-19 of Sichuan Province [2020YFS0006, 2020YFS0010]
- fast-track grants of SARS-CoV-2 research from West China Hospital, Sichuan University [HX-2019-nCoV-053, HX-2019-nCoV039]
- National Natural Science Foundation of China [81930125, 00402354A1028]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
- Fundamental Research Funds for the Central Universities [20822041D4060]
- National Key R&D Program of China [2020YFC0842000]
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The study designed and synthesized 32 new M-pro inhibitors containing bicycloproline, which showed inhibitory effects on SARS-CoV-2. Compounds MI-09 and MI-30 exhibited excellent antiviral activity in cell-based assays and significantly reduced lung viral loads and lung lesions in a transgenic mouse model of SARS-CoV-2 infection. Both also displayed good pharmacokinetic properties and safety in rats.
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 themost potent compounds, revealed its interactionmode. 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 withMI-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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