Human coronavirus HKU1 3C-like protease (3CLpro)

The Human coronavirus HKU1 3C-like protease (3CLpro), also referred to as the main protease (Mpro), is a critical enzyme for the replication of HCoV-HKU1, a betacoronavirus associated with human respiratory infections [1, 4]. It functions as a homodimeric cysteine protease that processes the viral polyproteins pp1a and pp1ab at eleven distinct sites to release functional non-structural proteins (nsps) essential for the viral replication-transcription complex [2, 6]. Because the enzyme specifically cleaves substrates after a glutamine residue—a motif not recognized by human host proteases—it is a primary target for the development of highly specific antiviral therapies with low host toxicity [6, 8]. HCoV-HKU1 typically causes self-limiting upper respiratory tract infections but can progress to severe pneumonia or bronchiolitis in children, the elderly, and immunocompromised patients [5, 10]. Therapeutic strategies focus on small-molecule inhibitors, such as the peptidomimetic N3 or natural products like baicalein, which bind to the catalytic dyad (Cys145 and His41) to block enzymatic activity [1, 13]. Due to the high conservation of the 3CLpro active site across coronaviruses, broad-spectrum inhibitors like GC376 and nirmatrelvir are often explored for their cross-reactivity against HCoV-HKU1 [8, 9, 14].

Other names

Main proteaseMpronsp53C-like proteinase3C-like cysteine protease

Inhibition of the viral 3C-like protease (3CLpro) by binding to the catalytic Cys-His dyad, thereby preventing the proteolytic processing of viral polyproteins and halting viral replication [1, 6, 8].