Main protease of severe acute respiratory syndrome coronavirus 2 (Mpro (also: 3CLpro))

The main protease of SARS-CoV-2 (Mpro, also known as 3CLpro) is a cysteine protease that is essential for the viral replication cycle. It functions by cleaving the large viral polyproteins pp1a and pp1ab at 11 conserved sites, thereby yielding multiple nonstructural proteins vital for the assembly of the viral replication and transcription machinery. Mpro is a homodimer composed of three structural domains, with a cys-his catalytic dyad and a substrate-binding site located at the interface of domains I and II. As it shares little homology with human proteases and is highly conserved across coronaviruses, Mpro is considered an ideal therapeutic target for direct-acting antivirals developed to treat COVID-19. Multiple small molecule inhibitors, including the clinically authorized nirmatrelvir, have been developed to selectively block Mpro activity, leading to inhibition of viral replication. The protease's substrate preferences, conserved structure, and role in polyprotein processing underscore its central importance in coronavirus biology and antiviral drug discovery.

Other names

Main protease (Mpro)3C-like protease (3CLpro)3-chymotrypsin-like proteaseSARS-CoV-2 main proteasensp5 (nonstructural protein 5)

Covalent binding to active site cysteine (Cys145), blocking substrate access and enzymatic proteolysis Reversible inhibition, preventing cleavage of viral polyproteins Restoration of host immune response (for some inhibitors such as D-4-77) Disruption of viral replication by preventing maturation of essential viral nonstructural proteins