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

The papain-like protease (PLpro) is a cysteine protease domain within nonstructural protein 3 (Nsp3) of SARS-CoV-2, and is essential for viral replication and pathogenesis[1][3]. PLpro processes the viral polyprotein by cleaving three specific sites to liberate Nsp1, Nsp2, and Nsp3, facilitating formation of the replication-transcription complex[1][3]. It is highly conserved among coronaviruses and structurally resembles cellular deubiquitinases, such as USP14 and USP7[5]. Beyond polyprotein cleavage, PLpro modulates host immune responses by functioning as a deubiquitinase and deISGylase, antagonizing interferon signaling[7]. PLpro is considered a prime therapeutic target in COVID-19 drug development because its inhibition blocks viral replication and immune evasion[1][4][6]. Several small-molecule inhibitors, including GRL0617, 5c, and naphthyridine derivatives, demonstrate potent in vitro antiviral activity and are under investigation as treatment options[4][6][8]. Safety concerns center on developing selectivity and minimizing cytotoxicity, as well as avoiding viral resistance[8].

Other names

SARS-CoV-2 PLproNsp3 papain-like proteaseSARS-CoV-2 papain-like protease domainSARS-CoV-2 PLpro proteasensp3 PLproPLpro protease

Competitive inhibition at the active site, blocking substrate recognition (peptidomimetic or noncovalent inhibitor); Covalent modification of active site cysteine (for some inhibitors); Preventing cleavage of viral polyproteins required for virus assembly/replication; Disrupting immune evasion via inhibition of deubiquitinase/deISGylase activity