Selective covalent targeting of SARS-CoV-2 main protease by enantiopure chlorofluoroacetamide

Daiki Yamane, Satsuki Onitsuka, Suyong Re, Hikaru Isogai, Rui Hamada, Tadanari Hiramoto, Eiji Kawanishi, Kenji Mizuguchi, Naoya Shindo, Akio Ojida

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

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 (Mpro) is a promising target for COVID-19 treatment. Here, we report an irreversible SARS-CoV-2 Mproinhibitor possessing chlorofluoroacetamide (CFA) as a warhead for the covalent modification of Mpro. 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 Mpro. Among the four stereoisomers, (R,R)-18 exhibited a markedly higher inhibitory activity against Mprothan 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 Mpro. 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.

Original languageEnglish
Pages (from-to)3027-3034
Number of pages8
JournalChemical Science
Volume13
Issue number10
DOIs
Publication statusPublished - Feb 15 2022

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

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