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

The Human coronavirus NL63 3C-like proteinase (3CLpro), also known as the main protease (Mpro) or nsp5, is a critical enzyme for the replication and transcription of the HCoV-NL63 virus [1, 3]. It is a cysteine protease that functions as a homodimer to cleave the large viral replicase polyproteins (pp1a and pp1ab) at eleven distinct sites, releasing essential non-structural proteins required for the viral life cycle [1, 4]. HCoV-NL63 is a common human respiratory pathogen associated with a range of illnesses, from the common cold to more severe conditions such as croup, bronchiolitis, and pneumonia, particularly in children and immunocompromised individuals [2, 3, 12]. Because of its indispensable role in the viral life cycle and its high conservation across the Coronaviridae family, 3CLpro is a primary target for the development of broad-spectrum antiviral drugs [3, 5, 8]. Inhibitors such as MK-7845 and GC376 target the catalytic cysteine residue within the enzyme's active site, effectively blocking viral replication [5, 8]. While no specific 3CLpro inhibitors are currently approved specifically for HCoV-NL63, the enzyme's unique substrate specificity—recognizing a glutamine residue at the P1 position—makes it an attractive target with potentially low off-target effects on host cell proteases [5].

Other names

Main proteaseMpronsp5Non-structural protein 53-Chymotrypsin-like protease

Inhibition of the viral 3C-like protease, which prevents the cleavage of the replicase polyproteins pp1a and pp1ab, thereby blocking the production of functional non-structural proteins essential for viral replication and transcription [1, 3, 5].