Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors.

ABSTRACT: The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PL^pro, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70^Ub binding site in PL^pro, we designed covalent PL^pro inhibitors by connecting cysteine reactive warheads to the biarylphenyl PL^pro inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC₅₀ = 0.1-0.3 μM) and antiviral activity (EC_50</

SUBMITTER: Tan B 

PROVIDER: S-EPMC12182049 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature