期刊
CHEMICAL SCIENCE
卷 13, 期 10, 页码 3027-3034出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d1sc06596c
关键词
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资金
- ''Chemistry for Multimolecular Crowding Biosystems (JSPS KAKENHI) [JP17H06349]
- AMED [JP18am0101091, JP21ak0101121, JP20.0108519]
- JSPS KAKENHI [19H02854]
- Sumitomo Foundation
- Grants-in-Aid for Scientific Research [19H02854] Funding Source: KAKEN
This study reports an irreversible inhibitor of SARS-CoV-2 M-pro with chlorofluoroacetamide (CFA) as a covalent modification agent. The (R,R)-18 isomer showed higher inhibitory activity against M-pro than other isomers. The findings highlight the influence of CFA chirality on the covalent modification of proteinous cysteines and provide a basis for improving the potency and selectivity of CFA-based covalent inhibitors.
The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (M-pro) is a promising target for COVID-19 treatment. Here, we report an irreversible SARS-CoV-2 M-pro inhibitor possessing chlorofluoroacetamide (CFA) as a warhead for the covalent modification of M-pro. Ugi multicomponent reaction using chlorofluoroacetic acid enabled the rapid synthesis of dipeptidic CFA derivatives that identified 18 as a potent inhibitor of SARS-CoV-2 M-pro. Among the four stereoisomers, (R,R)-18 exhibited a markedly higher inhibitory activity against M-pro than the other isomers. Reaction kinetics and computational docking studies suggest that the R configuration of the CFA warhead is crucial for the rapid covalent inhibition of M-pro. Our findings highlight the prominent influence of the CFA chirality on the covalent modification of proteinous cysteines and provide the basis for improving the potency and selectivity of CFA-based covalent inhibitors.
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