3C-like proteinase of SARS-CoV-2 (3CLpro (also commonly Mpro))

The 3C-like proteinase of SARS-CoV-2, also known as 3CLpro or the main protease (Mpro), is an essential cysteine protease required for coronavirus replication. It is encoded by the viral genome as part of the nonstructural protein 5 (nsp5) and processes the viral polyproteins pp1a and pp1ab by cleaving them at 11 conserved sites, releasing functional nonstructural proteins necessary for viral RNA synthesis and assembly. The enzyme has a chymotrypsin-like fold comprising three domains: domains I and II (β-barrels) form the substrate-binding site and carry the catalytic dyad (Cys145 and His41), while domain III (α-helical) mediates dimerization required for activity. Its substrate specificity (requiring a glutamine at the P1 position followed by small residues) makes it distinct from human proteases, enabling selective antiviral drug targeting. Inhibitors of this protease, such as nirmatrelvir, effectively block viral replication and have been developed as COVID-19 therapeutics[1][2][3][5][6].

Other names

Main protease (Mpro)SARS-CoV-2 main proteinaseNonstructural protein 5 (nsp5)Coronavirus main proteaseC30 endopeptidase

Inhibition of the active site cysteine-histidine catalytic dyad blocks cleavage of viral polyprotein, thereby inhibiting viral replication and preventing formation of essential nonstructural proteins [2][5][6]