Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.

ABSTRACT: The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication and for allowing the virus to evade the host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due to PLpro's restricted substrate binding pocket. In this report, we screened a 115 000-compound library for PLpro inhibitors and identified a new pharmacophore, based on a mercapto-pyrimidine fragment that is a reversible covalent inhibitor (RCI) of PLpro and inhibits viral replication in cells. Compound 5 had an IC₅₀ of 5.1 μM for PLpro inhibition and hit optimization yielded a derivative with increased potency (IC₅₀ 0.85 μM, 6-fold higher). Activity based profiling of compound

SUBMITTER: Bajaj T 

PROVIDER: S-EPMC10259201 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature