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SARS-CoV-2 Mpro oligomerization as a potential target for therapy.
Int. J. Biol. Macromol. 267:131392 (2024)
Verlagsversion
DOI
PMC
The main protease (Mpro) of SARS-CoV-2 is critical in the virus's replication cycle, facilitating the maturation of polyproteins into functional units. Due to its conservation across taxa, Mpro is a promising target for broad-spectrum antiviral drugs. Targeting Mpro with small molecule inhibitors, such as nirmatrelvir combined with ritonavir (Paxlovid™), which the FDA has approved for post-exposure treatment and prophylaxis, can effectively interrupt the replication process of the virus. A key aspect of Mpro's function is its ability to form a functional dimer. However, the mechanics of dimerization and its influence on proteolytic activity remain less understood. In this study, we utilized biochemical, structural, and molecular modelling approaches to explore Mpro dimerization. We evaluated critical residues, specifically Arg4 and Arg298, that are essential for dimerization. Our results show that changes in the oligomerization state of Mpro directly affect its enzymatic activity and dimerization propensity. We discovered a synergistic relationship influencing dimer formation, involving both intra- and intermolecular interactions. These findings highlight the potential for developing allosteric inhibitors targeting Mpro, offering promising new directions for therapeutic strategies.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Dimerization ; M(pro) ; Sars-cov-2; Respiratory Syndrome Coronavirus; 3c-like Protease; Main Protease; Dimerization; Catalysis; Dimer; Visualization; Mechanism; Efficient; Reveals
ISSN (print) / ISBN
0141-8130
e-ISSN
1879-0003
Quellenangaben
Band: 267,
Artikelnummer: 131392
Verlag
Elsevier
Verlagsort
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Structural Biology (STB)
Förderungen
National Science Center
Innovative Medicines Initiative two Joint Undertaking (JU)
DURABLE project
European Union
National Science Centre
NAWA Polish Returns 2018
Foundation for Polish Science
Polish Ministry of Science and Higher Education
Innovative Medicines Initiative two Joint Undertaking (JU)
DURABLE project
European Union
National Science Centre
NAWA Polish Returns 2018
Foundation for Polish Science
Polish Ministry of Science and Higher Education