Severe acute respiratory syndrome coronavirus 2 main protease (Mpro) (Mpro)

The Severe acute respiratory syndrome coronavirus 2 main protease (Mpro), also known as 3CLpro, is a critical cysteine protease essential for the life cycle of the SARS-CoV-2 virus [1, 3]. It is responsible for the proteolytic processing of the large viral polyproteins, pp1a and pp1ab, at eleven distinct sites to release functional non-structural proteins (nsps) required for viral replication and transcription [4, 5]. Because Mpro is highly conserved among coronaviruses and lacks a human homolog, it serves as an ideal target for antiviral drug development with a high degree of selectivity [1, 10]. Drugs such as nirmatrelvir and ensitrelvir function by binding to the enzyme's active site, often forming a covalent bond with the catalytic Cys145 residue, which effectively blocks its proteolytic activity [3, 5]. Clinical use of these inhibitors has demonstrated significant efficacy in reducing viral load and preventing severe disease progression in COVID-19 patients [3, 14]. However, challenges such as drug-drug interactions, particularly when co-administered with ritonavir, and the emergence of resistance-conferring mutations like E166V remain important considerations for long-term therapeutic success [5]. Ongoing research continues to explore non-covalent inhibitors and dual-targeting agents to overcome these limitations and provide broader protection against emerging variants [5, 10].

Other names

3C-like protease3CLproMpronsp5SARS-CoV-2 3CL proteaseCOVID-19 main protease3C-like proteinase

The drugs target the SARS-CoV-2 main protease (Mpro) by binding to its active site, specifically the catalytic dyad consisting of His41 and Cys145 [1, 10]. This binding, which can be covalent (e.g., nirmatrelvir) or non-covalent (e.g., ensitrelvir), inhibits the enzyme's ability to cleave the viral polyproteins pp1a and pp1ab into functional non-structural proteins, thereby effectively halting viral replication and assembly [3, 5].