Severe acute respiratory syndrome coronavirus 2 3C-like protease (3CLpro)

The SARS-CoV-2 3C-like protease (3CLpro), also known as the main protease (Mpro), is a critical enzyme for the replication of the severe acute respiratory syndrome coronavirus 2 [1, 2]. It is a cysteine protease that functions as a homodimer, responsible for cleaving the large viral polyproteins pp1a and pp1ab at eleven specific sites to release functional non-structural proteins (nsps 4-16) [2, 7]. These nsps are essential for the assembly of the viral replication-transcription complex [7, 9]. Because 3CLpro has no closely related human homologs and possesses a unique substrate specificity, it is a highly attractive target for antiviral therapy with a high safety margin [5, 12]. Drugs such as nirmatrelvir and ensitrelvir target this enzyme by binding to its active site, often forming a covalent bond with the catalytic cysteine residue (Cys145), thereby halting the viral life cycle [6, 12]. Clinical use of these inhibitors has been effective in reducing hospitalization and death in high-risk COVID-19 patients, although challenges such as drug-drug interactions and the potential for emergent resistance mutations remain [1, 12].

Other names

Main proteaseMpronsp5C30 endopeptidaseSARS-CoV-2 main protease3-chymotrypsin-like protease

Inhibition of the 3C-like protease prevents the cleavage of the viral polyproteins pp1a and pp1ab into functional non-structural proteins, which are essential for viral replication and transcription [1, 9].