SARS-CoV-2 papain-like protease and 3-chymotrypsin-like protease (PLpro and 3CLpro)

This entry refers to two distinct viral proteases, PLpro and 3CLpro, which are separate enzymes encoded by different regions of the viral genome (NSP3 and NSP5, respectively) [2, 3]. SARS-CoV-2 papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro, also known as the main protease or Mpro) are two essential viral enzymes required for the maturation and replication of the SARS-CoV-2 virus [1, 2]. These cysteine proteases are responsible for cleaving the large viral polyproteins (pp1a and pp1ab) into functional non-structural proteins (nsps) that form the viral replication-transcription complex [10, 12]. While 3CLpro performs the majority of the cleavage events (11 sites), PLpro is responsible for three specific cleavages and possesses additional deubiquitinating and deISGylating activities that help the virus evade the host's innate immune response by antagonizing interferon signaling [3, 15]. Because these enzymes are critical for the viral life cycle and lack close human homologs, they are primary targets for antiviral drug development [16]. Drugs like nirmatrelvir and ensitrelvir specifically inhibit 3CLpro to halt viral replication, while PLpro inhibitors like GRL0617 are being actively researched to both block replication and restore host immune function [7, 12].

Other names

Main proteaseMproNSP5NSP3Papain-like protease3-chymotrypsin-like proteasePLPSARS-CoV-2 MproSARS-CoV-2 PLpro

Inhibition of viral cysteine protease activity by binding to the catalytic site (Cys145 in 3CLpro or Cys111 in PLpro), preventing the cleavage of viral polyproteins and subsequent viral replication [4, 16].