SARS-CoV-1 3C-like protease (3CLpro)

The SARS-CoV-1 3C-like protease (3CLpro), also known as the main protease (Mpro) or nsp5, is a 33-kDa cysteine protease essential for the life cycle of the Severe Acute Respiratory Syndrome coronavirus [2, 12]. It is responsible for the proteolytic processing of the large viral polyproteins, pp1a and pp1ab, at 11 distinct sites to release functional non-structural proteins (nsps 4–16) [1, 17]. These nsps subsequently assemble into the replication-transcription complex (RTC), which is required for viral genome replication and transcription [6, 12]. The enzyme functions as a homodimer, with each monomer containing a catalytic dyad composed of Cys145 and His41 [7, 12]. Because 3CLpro recognizes a specific cleavage sequence (Leu-Gln↓(Ser, Ala, Gly)) that is not utilized by any known human host proteases, it is a primary target for antiviral drug development [13, 18]. During the 2003 SARS outbreak, protease inhibitors such as lopinavir and ritonavir were repurposed for clinical use, and various peptidomimetic inhibitors like rupintrivir and AG7404 were investigated for their ability to block the active site [3, 14]. Inhibition of 3CLpro effectively halts viral replication by preventing the maturation of the replication machinery [9, 17]. Beyond its role in replication, 3CLpro has been implicated in inducing host cell apoptosis through the activation of caspase-3 and caspase-9 pathways [16].

Other names

Main proteaseMpronsp53C-like proteinaseSARS-CoV 3CLproSARS-CoV Mpro

Inhibition of viral polyprotein cleavage at 11 conserved sites, preventing the maturation of non-structural proteins and the assembly of the viral replication-transcription complex.