Papain-like protease, SARS-CoV-2 (PLpro)

Papain-like protease, SARS-CoV-2 (PLpro) is a cysteine protease domain within non-structural protein 3 (Nsp3) of SARS-CoV-2, essential for viral replication due to its proteolytic processing of the viral polyproteins pp1a and pp1ab, releasing non-structural proteins required for assembly of the viral replicase-transcriptase complex[1][4][5]. PLpro has a canonical architecture reminiscent of deubiquitinases, with thumb, palm, and fingers domains, and an active site comprising a Cys-His-Asp catalytic triad[2][3][4]. Beyond its role in viral peptide cleavage, PLpro exerts deubiquitinating and deISGylating activities, removing ubiquitin and ISG15 modifications from host proteins, which allows the virus to antagonize the host innate immune response[3][4][5]. Due to its critical, multitargeted functions, PLpro is considered a prime therapeutic target for antiviral drug development, and several protease inhibitors, including GRL-0617 and related compounds, have shown the ability to inhibit its enzymatic activity and suppress SARS-CoV-2 replication in vitro[1][5].

Other names

SARS-CoV-2 PLproPL^proSARS-CoV-2 papain-like proteaseCoronavirus papain-like proteaseNsp3 papain-like protease domain

Inhibition of the proteolytic (peptidase) activity to block processing of viral polyproteins; Allosteric inhibition by preventing substrate or cofactor binding; Disruption of deubiquitination/deISGylation to restore host innate immunity