SARS-CoV-2 viral proteases (Mpro/PLpro)

SARS-CoV-2 viral proteases, specifically the main protease (Mpro or 3CLpro) and the papain-like protease (PLpro), are essential enzymes for the replication and maturation of the SARS-CoV-2 virus (NIH, 2020). These cysteine proteases are responsible for cleaving the large viral polyproteins, pp1a and pp1ab, into 16 functional non-structural proteins (Nsps) that form the viral replication-transcription complex (UniProt, 2021). Mpro (nsp5) cleaves the polyprotein at 11 distinct sites, while PLpro (a domain of nsp3) cleaves at 3 sites and also possesses deubiquitinating and deISGylating activities that help the virus evade the host's innate immune response (PubMed, 2021). Because these proteases have no human homologs with the same cleavage specificity, they are highly attractive targets for antiviral drug development (RCSB PDB, 2020). Drugs such as nirmatrelvir and ensitrelvir target Mpro to inhibit viral replication, while PLpro inhibitors like GRL-0617 are currently under investigation (NIH, 2022). Therapeutic challenges include significant drug-drug interactions, particularly when Mpro inhibitors are co-administered with ritonavir, and the potential for viral resistance due to mutations in the protease genes (PubMed, 2024).

Other names

3C-like protease3CLproMain proteaseMproPapain-like proteasePLproNon-structural protein 5nsp5Non-structural protein 3nsp33-chymotrypsin-like proteaseSARS-CoV-2 3CLproSARS-CoV-2 PLpro

Protease inhibition; drugs bind to the catalytic active sites of the viral proteases (typically the Cys-His dyad) to prevent the cleavage of viral polyproteins into functional non-structural proteins, thereby halting the viral replication cycle.