Human coronavirus HKU1 main protease (HKU1-Mpro) (HKU1-Mpro)

The Human coronavirus HKU1 main protease (HKU1-Mpro), also referred to as 3C-like proteinase (3CLpro) or non-structural protein 5 (nsp5), is an essential enzyme for the life cycle of the HKU1 coronavirus, which primarily causes upper and lower respiratory tract infections (UniProt P0C6X2). This cysteine protease operates as a homodimer and is responsible for the proteolytic processing of the viral polyproteins pp1a and pp1ab at eleven distinct sites, releasing functional proteins necessary for viral RNA synthesis and replication (PubMed: 16840320). Because its substrate specificity—cleaving after a glutamine residue—is distinct from known human proteases, it serves as a high-priority target for the development of specific antiviral drugs with minimal off-target effects (PubMed: 32355360). Therapeutic strategies involve small-molecule inhibitors, such as nirmatrelvir or experimental compounds like GC376, which bind to the active site and block the catalytic Cys-His dyad (PubMed: 36302775). Research into HKU1-Mpro is vital for the development of broad-spectrum pan-coronavirus inhibitors that can provide preparedness against both seasonal and emergent coronaviral threats.

Other names

3C-like proteinase3CLproMproNon-structural protein 5nsp5HKU1-CoV 3CLpro

Inhibition of the viral main protease prevents the cleavage of polyproteins pp1a and pp1ab into functional non-structural proteins, thereby halting viral replication.