SARS-CoV-2 papain-like protease (PLpro)

SARS-CoV-2 papain-like protease (PLpro) is a viral cysteine protease and a critical domain within non-structural protein 3 (nsp3) of the SARS-CoV-2 virus. It plays a dual role in coronavirus replication: (1) proteolytically cleaving viral polyproteins at specific sites to release functional nsp1, nsp2, and nsp3, which are necessary for assembly of the viral replication-transcription complex, and (2) counteracting host immune responses by removing ubiquitin and ISG15 modifications from host proteins (deubiquitinase and deISGylase activities), thereby suppressing interferon-mediated antiviral signaling and aiding viral evasion of innate immunity. PLpro is highly conserved among coronaviruses, essential for viral life cycle, and is considered an attractive antiviral drug target. Multiple structurally characterized small-molecule inhibitors have been identified, and some, such as GRL-0617 and novel quinoline derivatives (e.g., Jun12682, Jun13296), show antiviral efficacy in preclinical models. Inhibitor development is challenged by the fast mutation rate of the virus and functional overlap with host deubiquitinases, requiring careful balance between antiviral potency and selectivity[1][2][3][4][6][7][8].

Other names

Papain-like protease (PLpro)Non-structural protein 3 papain-like protease domain (nsp3-PLpro)EC 3.4.22.46

Inhibition of viral polyprotein processing by binding to PLpro active or allosteric site, preventing the release of essential replicase proteins Blockade of deubiquitinase/deISGylase activities, restoring host antiviral immune responses[2][3][4][6]