SARS-CoV-2 main protease (Mpro) (Mpro; PLpro)

SARS-CoV-2 proteases are critical viral enzymes required for the maturation of the viral replicase complex and the production of functional non-structural proteins (nsps). This target class primarily includes two distinct cysteine proteases: the main protease (Mpro, also known as 3C-like protease or 3CLpro) and the papain-like protease (PLpro) [1, 4]. Mpro, encoded by nsp5, is a homodimeric enzyme that cleaves the viral polyproteins at 11 conserved sites, whereas PLpro, a domain of nsp3, cleaves at three N-terminal sites and further acts as a deubiquitinase and deISGylase enzyme to suppress host innate immunity [7, 13, 21]. Because these enzymes are essential for viral replication and maturation and possess distinct substrate specificities relative to human proteases, they are prime targets for antiviral development [11, 15]. Major approved drugs like nirmatrelvir (the active component of Paxlovid) and ensitrelvir target the catalytic center of Mpro (specifically the Cys145 residue) to irreversibly or reversibly block enzyme activity, effectively halting the viral life cycle [2, 17, 22]. While Mpro is currently the most clinically advanced target, PLpro is also an active area of investigation for dual-action inhibitors that can both block replication and restore the host's innate immune response [5, 10, 19].

Other names

3C-like protease (3CLpro)Main protease (Mpro)Papain-like protease (PLpro)SARS-CoV-2 nsp5 proteaseSARS-CoV-2 nsp3 protease domainCoronavirus 3C-like protease3-chymotrypsin-like protease

Covalent or non-covalent inhibition of the viral cysteine protease active site (e.g., Cys145 in Mpro or Cys111 in PLpro), preventing the proteolytic cleavage of viral polyproteins pp1a and pp1ab into functional non-structural proteins, thereby blocking viral replication and maturation [2, 10, 16, 21].