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Lis, K.* ; Plewka, J.* ; Cardoso Micu Menezes, F.M. ; Bielecka, E.* ; Chykunova, Y.* ; Pustelny, K.* ; Niebling, S.* ; Garcia, A.S.* ; Garcia-Alai, M.* ; Popowicz, G.M. ; Czarna, A.* ; Kantyka, T.* ; Pyrc, K.*

SARS-CoV-2 Mpro oligomerization as a potential target for therapy.

Int. J. Biol. Macromol. 267:131392 (2024)
DOI PMC
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 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
Journal International Journal of Biological Macromolecules
Quellenangaben Volume: 267, Issue: , Pages: , Article Number: 131392 Supplement: ,
Publisher Elsevier
Publishing Place Radarweg 29, 1043 Nx Amsterdam, Netherlands
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants 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