A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals.

ABSTRACT: As an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (M^Pro) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl M^Pro inhibitors that contained also an aldehyde warhead and β-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray crystal structures of their complexes with M^Pro, their inhibition of M^Pro transiently expressed in 293T cells, and cellular toxicity and SARS-CoV-2 antiviral potency of selected inhibitors. These inhibitors have a large variation of

SUBMITTER: Ma Y 

PROVIDER: S-EPMC9235293 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature