Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease.

ABSTRACT: Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (M^pro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the M^pro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor's keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the M^pro acti

SUBMITTER: Kneller DW 

PROVIDER: S-EPMC9046211 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature