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

The Human coronavirus NL63 3C-like protease (3CLpro), also referred to as the main protease (Mpro) or non-structural protein 5 (nsp5), is an essential enzyme for the replication of the HCoV-NL63 virus (UniProt: P0C6U5). It functions by cleaving the large viral polyproteins, pp1a and pp1ab, at multiple conserved sites to release functional non-structural proteins necessary for the viral replication-transcription complex (Lin et al., 2005). HCoV-NL63 is a significant human pathogen, particularly known for causing croup in children and various other respiratory tract infections (NIH). Because the substrate specificity of 3CLpro—specifically its preference for glutamine at the P1 position—is distinct from known human proteases, it serves as a highly selective target for antiviral drug development (Wang et al., 2020). Small molecule inhibitors, such as the experimental drug GC376 and the repurposed protease inhibitor boceprevir, target the enzyme's active site to block its catalytic activity (Kim et al., 2012; Ma et al., 2020). Successfully inhibiting this protease effectively halts the production of mature viral proteins, thereby stopping the viral life cycle. Therapeutic challenges include the potential for the virus to develop resistance through mutations in the protease gene and the need for high drug bioavailability in the respiratory tract (PubMed).

Other names

Main proteaseMproNon-structural protein 5nsp5HCoV-NL63 3CLpro

Inhibition of the viral main protease by binding to the catalytic cysteine residue, preventing the cleavage of viral polyproteins into functional units (Kim et al., 2012).