Potent and Selective Covalent Inhibition of the Papain-like Protease from SARS-CoV-2.

ABSTRACT: Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 is essential for viral replication. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophile onto analogs of the noncovalent PLpro inhibitor GRL0617. The most potent compound inhibited PLpro with k_inact/K_I = 10,000 M^-

SUBMITTER: Sanders B 

PROVIDER: S-EPMC8509099 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature