SARS coronavirus 3C-like protease (3CLpro)

SARS coronavirus 3C-like protease (3CLpro), also known as the main protease (Mpro), is an essential enzyme for the life cycle of coronaviruses, including SARS-CoV and SARS-CoV-2 [1, 6]. It is a homodimeric cysteine protease that cleaves the large viral polyproteins, pp1a and pp1ab, at eleven conserved sites to release functional non-structural proteins (nsps) such as the RNA-dependent RNA polymerase [12, 13]. Because 3CLpro has no human homologs and exhibits a unique substrate preference for glutamine at the P1 position, it is a highly attractive target for selective antiviral therapy [1, 7]. Drugs like nirmatrelvir and ensitrelvir inhibit this enzyme by binding to its active site, specifically targeting the Cys145-His41 catalytic dyad, which halts viral replication and reduces viral load in patients [12, 15]. Beyond its role in replication, 3CLpro may also modulate host immune responses by cleaving cellular proteins involved in innate immunity [11, 13]. Therapeutic challenges include the risk of drug-drug interactions when co-administered with pharmacokinetic enhancers like ritonavir and the potential emergence of resistance mutations in the protease gene [1, 12].

Other names

Main proteaseMpro3C-like proteasensp5C30 endopeptidaseSARS-CoV 3CLproSARS-CoV-2 3CLproSARS coronavirus main proteinase

Inhibition of the 3C-like protease activity by binding to the catalytic dyad (Cys145 and His41), which prevents the cleavage of viral polyproteins into functional non-structural proteins, thereby blocking viral replication and maturation [1, 3, 7, 13].