3C-like proteinase (3CLpro) (3CLpro)

The 3C-like proteinase (3CLpro), also known as the main protease (Mpro) or non-structural protein 5 (nsp5), is an essential enzyme for the replication of the SARS-associated coronavirus (SARS-CoV) [1, 14]. It is a cysteine protease that functions as a homodimer, utilizing a catalytic dyad of Cys145 and His41 to cleave the large viral polyproteins, pp1a and pp1ab, at eleven specific sites [4, 14]. This proteolytic processing is required to release functional non-structural proteins that form the viral replicase-transcriptase complex [10, 12]. Because 3CLpro has a unique substrate specificity—cleaving after a glutamine residue—and no known human proteases share this requirement, it is a highly attractive and selective target for antiviral therapy [1, 2]. Drugs targeting this enzyme, such as nirmatrelvir and various peptidomimetics, act by binding to the active site and inhibiting its catalytic activity, thereby halting the production of infectious virus particles [8, 10]. In addition to its role in replication, 3CLpro has been implicated in antagonizing the host's innate immune response by degrading key signaling proteins like IRF3 [15]. Consequently, 3CLpro inhibitors not only reduce viral load but may also help restore host immune defenses during infection [10, 15].

Other names

Main proteaseMproNon-structural protein 5nsp5C30 endopeptidaseSARS-CoV 3CLpro

Inhibition of the catalytic activity of the protease by binding to the active site (Cys145/His41 dyad), preventing the cleavage of viral polyproteins pp1a and pp1ab into functional non-structural proteins.