SARS-CoV-2 Main Protease and Papain-like Protease (Mpro and PLpro)

SARS-CoV-2 Main Protease (Mpro) and Papain-like Protease (PLpro) are essential cysteine proteases encoded by the SARS-CoV-2 genome (UniProt P0DTD1). Mpro, or 3C-like protease (3CLpro), cleaves the viral polyproteins pp1a and pp1ab at 11 sites to generate functional non-structural proteins (nsps) 4 through 16 (Jin et al., Nature 2020). PLpro, a domain within nsp3, cleaves the polyprotein at three sites to release nsp1, nsp2, and nsp3 (Shin et al., Nature 2020). Additionally, PLpro acts as a deubiquitinating and deISGylating enzyme, which suppresses the host's innate immune response by removing ubiquitin and ISG15 from host proteins involved in interferon signaling (Klemm et al., EMBO J 2020). These enzymes are critical therapeutic targets; Mpro inhibitors like nirmatrelvir (part of Paxlovid) and ensitrelvir are clinically used to treat COVID-19 by halting viral replication (Owen et al., Science 2021). While no PLpro inhibitors are currently FDA-approved, they represent a dual-action strategy to inhibit replication and boost host immunity (Rut et al., Nat Commun 2020).

Other names

3C-like protease3CLpronsp5nsp3Papain-like proteaseSARS-CoV-2 3CLproSARS-CoV-2 PLpro

Inhibition of viral cysteine proteases (Mpro and PLpro), preventing the cleavage of viral polyproteins into functional units and, in the case of PLpro, inhibiting viral deubiquitination and deISGylation to restore host immune responses.