Papain-like protease nsp3 (PLpro) (PLpro)

The SARS-CoV papain-like protease (PLpro) is an essential multifunctional enzyme encoded within the non-structural protein 3 (nsp3) of coronaviruses, including SARS-CoV and SARS-CoV-2 [1, 2]. Its primary role is the proteolytic processing of the viral polyproteins pp1a and pp1ab, specifically cleaving the N-terminal sites to release nsp1, nsp2, and nsp3, which are critical for the assembly of the viral replicase-transcriptase complex [4, 11]. Beyond its proteolytic function, PLpro acts as a deubiquitinating (DUB) and deISGylating enzyme, removing ubiquitin and ISG15 modifications from host proteins to antagonize the innate immune response and suppress interferon production [3, 6]. This dual role in viral replication and immune evasion makes PLpro a high-priority target for antiviral drug development [9, 16]. Therapeutic strategies focus on small-molecule inhibitors, such as GRL-0617 and various repurposed drugs, which aim to block the enzyme's active site or its interaction with host substrates [7, 14]. Effective inhibition of PLpro not only halts viral spread but also potentially restores the host's ability to mount an effective antiviral immune response [2, 16]. Structurally, the enzyme features a characteristic right-handed thumb-palm-fingers architecture and a catalytic triad that recognizes the LXGG motif [5, 10]. While highly conserved, differences in substrate preference between SARS-CoV and SARS-CoV-2 PLpro have been noted, with the latter showing enhanced deISGylation activity [2, 16].

Other names

PL-PROPL2-PROnsp3 proteasePapain-like protease domain of non-structural protein 3SARS-CoV papain-like protease

Inhibition of the catalytic activity of the papain-like protease, either through non-covalent binding to the S3/S4 subsites and BL2 loop or through covalent modification of the catalytic cysteine residue (Cys111 in SARS-CoV-2, Cys1651 in SARS-CoV polyprotein), thereby preventing viral polyprotein processing and host immune evasion [7, 14, 17].