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

The **main protease of severe acute respiratory syndrome coronavirus 2 (Mpro or 3CLpro)** is an essential cysteine protease required for the proteolytic cleavage of the virus’s large replicase polyproteins (pp1a and pp1ab) into functional nonstructural proteins, a crucial process for viral genome replication and transcription[2][3][5][7][9]. This enzyme is a homodimer, each protomer organized into three structural domains. The active site—containing a catalytic dyad (Cys145 and His41)—selectively recognizes and cleaves conserved Gln↓(Ser, Ala, Gly) peptide bond motifs at 11 distinct sites in the polyprotein[3][5]. Because of its essential and non-redundant function in the viral life cycle and lack of close human homologs, Mpro is an attractive and validated therapeutic target for antiviral drug discovery against COVID-19. Several classes of inhibitors—approved, repurposed, and investigational—directly inhibit Mpro by binding its substrate-binding site, often forming covalent adducts with the active-site cysteine, demonstrating strong antiviral effects in vitro and in vivo[2][3][6][8]. Note: SARS-CoV-2 also encodes a second essential protease, **papain-like protease (PLpro, part of Nsp3)**, which is also essential for replication and a potential target, but "SARS-CoV-2 protease" in biomedical literature almost universally refers to Mpro/3CLpro for drug discovery and structural studies[2][7].

Other names

Main protease (Mpro)3C-like protease (3CLpro)Nsp5 (nonstructural protein 5)SARS-CoV-2 main protease

Covalent, reversible, or competitive inhibition of the active site cysteine, thereby blocking substrate binding and cleavage essential for viral polyprotein maturation and replication[2][3][4][5][8].