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

• Published in: Chemical science (Cambridge) Vol. 13; no. 10; pp. 3027 - 3034
• Main Authors: Yamane, Daiki, Onitsuka, Satsuki, Re, Suyong, Isogai, Hikaru, Hamada, Rui, Hiramoto, Tadanari, Kawanishi, Eiji, Mizuguchi, Kenji, Shindo, Naoya, Ojida, Akio
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 09.03.2022; Royal Society of Chemistry; The Royal Society of Chemistry
• Subjects: Chemistry; Chemistry, Multidisciplinary; Chirality; Coronaviruses; Covalence; COVID-19; Inhibitors; Physical Sciences; Protease; Reaction kinetics; Science & Technology; Selectivity; Severe acute respiratory syndrome coronavirus 2; Stereoisomerism; Viral diseases; Warheads; DISCOVERY; INHIBITORS
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/D1SC06596C

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.