Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors.

ABSTRACT: SARS-CoV-2 main protease (M^pro) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant M^pro mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of M^pro inhibitors. In this study, we explored several reactive warheads in the design of M^pro inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent M^pro inhibitors. Jun10541R and Ju

SUBMITTER: Tan B 

PROVIDER: S-EPMC10529912 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature