3-chymotrypsin-like protease (3CLpro) (3CLpro)

The 3-chymotrypsin-like protease (3CLpro), also known as the main protease (Mpro) or non-structural protein 5 (nsp5), is a highly conserved cysteine protease essential for the replication of coronaviruses and noroviruses (UniProt P0DTD1; Jin et al., 2020, Nature). It is responsible for processing the large viral polyproteins, pp1a and pp1ab, into individual functional non-structural proteins that form the viral replication-transcription complex (Zhang et al., 2020, Science). Because 3CLpro cleaves at a specific glutamine-containing sequence that is not recognized by any known human host proteases, it is an exceptionally attractive target for the development of selective antiviral drugs with minimal off-target effects (NIH, 2023). In the context of the COVID-19 pandemic, 3CLpro became a primary focus for drug development, leading to the approval of inhibitors like nirmatrelvir, which effectively block the enzyme's catalytic activity (FDA, 2023; PubChem). Beyond coronaviruses, the 3CLpro of noroviruses (often termed NS6) performs a similar vital role in viral maturation, making it a target for treating severe viral gastroenteritis (Dang et al., 2021, Journal of Virology). The enzyme's structural conservation across different viral families suggests that 3CLpro inhibitors could serve as broad-spectrum antivirals against both current and emerging viral threats.

Other names

Main proteaseMproNon-structural protein 5nsp53C-like proteaseNS6 proteaseC30 Endopeptidase

Inhibition of the viral 3-chymotrypsin-like protease (3CLpro) prevents the cleavage of viral polyproteins (pp1a and pp1ab) into functional non-structural proteins, thereby halting the assembly of the viral replication-transcription complex and stopping viral replication (Jin et al., 2020, Nature; Zhang et al., 2020, Science).