A systematic exploration of boceprevir-based main protease inhibitors as SARS-CoV-2 antivirals.

ABSTRACT: Boceprevir is an HCV NSP3 inhibitor that was explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (M^Pro) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based M^Pro inhibitors including PF-07321332 and characterized their M^Pro inhibition potency in test tubes (in vitro) and 293T cells (in cellulo). Crystal structures of M^Pro bound with 10 inhibitors and cytotoxicity and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (Opal) residue and the warh

SUBMITTER: Alugubelli YR 

PROVIDER: S-EPMC9264725 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature