Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors.

ABSTRACT: The main protease (M^Pro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target M^Pro's catalytic cysteine. Our characterization identified potent M^Pro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC₅₀ value of 10 nM against SARS-CoV-2 infection in ACE2⁺ A549 cells and a selective index of 875. MPI89 is also remarkably selective an

SUBMITTER: Khatua K 

PROVIDER: S-EPMC11070182 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature