Severe acute respiratory syndrome coronavirus 1 3C-like protease (3CLpro)

The Severe acute respiratory syndrome coronavirus 1 3C-like protease (SARS-CoV-1 3CLpro), also known as the main protease (Mpro), is a critical enzyme for the replication of the SARS-CoV-1 virus. It is a cysteine protease that functions as a homodimer, utilizing a catalytic dyad of Cys145 and His41 to cleave the viral polyproteins pp1a and pp1ab at eleven distinct sites (1.2.1, 1.2.4). This proteolytic processing is essential for releasing functional non-structural proteins (nsps 4-16) that form the viral replicase-transcriptase complex (1.2.2, 1.3.1). Because 3CLpro has a unique substrate specificity—preferring a glutamine residue at the P1 position—which is not shared by known human proteases, it is considered an ideal target for highly specific antiviral drugs (1.2.4, 1.3.1). Therapeutic strategies involve the development of both covalent inhibitors, which form a bond with the catalytic cysteine, and non-covalent inhibitors that block the active site (1.1.1, 1.2.1). While no drugs were specifically approved for SARS-CoV-1 during the 2003 outbreak, the high conservation of this enzyme across coronaviruses has led to the repurposing and development of broad-spectrum inhibitors like nirmatrelvir (1.2.3, 1.4.3). Targeting 3CLpro effectively halts viral maturation and reduces viral load, offering a potent mechanism to combat coronavirus-associated respiratory diseases (1.3.1).

Other names

Main proteaseMpro3C-like proteasensp5SARS-CoV 3CLproSARS-CoV-1 main protease

Cysteine protease inhibition via covalent or non-covalent binding to the active site catalytic dyad (Cys145/His41), preventing viral polyprotein cleavage.