Human coronavirus NL63 3C-like protease (hCoV-NL63 3CLpro)

Human coronavirus NL63 3C-like protease (hCoV-NL63 3CLpro), also known as the main protease (Mpro) or nsp5, is a critical enzyme for the replication and maturation of the HCoV-NL63 virus [NIH, 2021; RCSB PDB]. HCoV-NL63 is an alphacoronavirus that causes a significant portion of common colds and more severe respiratory conditions like croup and bronchiolitis in pediatric and immunocompromised populations [Wikipedia; NIH, 2012]. The 3CLpro enzyme operates as a homodimer, employing a catalytic dyad of cysteine (Cys144) and histidine (His41) to cleave the viral polyproteins pp1a and pp1ab at eleven conserved sites [NIH, 2016; Wikipedia]. This proteolytic activity is indispensable for the release of non-structural proteins (nsps) required for the viral replication-transcription complex [NIH, 2020; MDPI, 2023]. Due to its unique substrate specificity—preferring glutamine at the P1 position—and the absence of human homologs with similar cleavage patterns, 3CLpro is a highly attractive target for antiviral therapy [NIH, 2021; Preprints.org, 2024]. Small molecule inhibitors, including covalent peptidomimetics like nirmatrelvir and experimental agents like GC376 and N3, bind to the active site to prevent polyprotein processing, thereby effectively halting viral replication [NIH, 2016; Preprints.org, 2024].

Other names

Main proteaseMpronsp5C30 endopeptidase3-chymotrypsin-like protease3-chymotrypsin-like proteinaseNon-structural protein 5

Covalent inhibition of the catalytic cysteine residue (Cys144), preventing the cleavage of viral polyproteins pp1a and pp1ab into functional non-structural proteins [NIH, 2016; NIH, 2021].