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

Autor: Lis K; Jagiellonian University, Malopolska Centre of Biotechnology, Virogenetics, Laboratory of Virology, Gronostajowa 7a, 30-387 Cracow, Poland; Faculty of Chemical Engineering and Technology, Cracow University of Technology, Warszawska 24,31-155 Cracow, Poland., Plewka J; Jagiellonian University, Malopolska Centre of Biotechnology, Virogenetics, Laboratory of Virology, Gronostajowa 7a, 30-387 Cracow, Poland., Menezes F; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany., Bielecka E; Jagiellonian University, Malopolska Centre of Biotechnology, Laboratory of Proteolysis and Post-translational Modification of Proteins, Gronostajowa 7a, 30-387 Cracow, Poland., Chykunova Y; Jagiellonian University, Malopolska Centre of Biotechnology, Virogenetics, Laboratory of Virology, Gronostajowa 7a, 30-387 Cracow, Poland; Jagiellonian University, Faculty of Biochemistry, Biophysics and Biotechnology, Microbiology Department, Gronostajowa 7, 30-387, Cracow, Poland., Pustelny K; Jagiellonian University, Malopolska Centre of Biotechnology, Gronostajowa 7a, 30-387 Cracow, Poland., Niebling S; European Molecular Biology Laboratory, EMBL Hamburg, Notkestrasse 85, Hamburg, Germany; Centre for Structural Systems Biology (CSSB), Hamburg, Germany., Garcia AS; European Molecular Biology Laboratory, EMBL Hamburg, Notkestrasse 85, Hamburg, Germany; Centre for Structural Systems Biology (CSSB), Hamburg, Germany., Garcia-Alai M; European Molecular Biology Laboratory, EMBL Hamburg, Notkestrasse 85, Hamburg, Germany; Centre for Structural Systems Biology (CSSB), Hamburg, Germany., Popowicz GM; Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany., Czarna A; Jagiellonian University, Malopolska Centre of Biotechnology, Gronostajowa 7a, 30-387 Cracow, Poland. Electronic address: anna1.czarna@uj.edu.pl., Kantyka T; Jagiellonian University, Malopolska Centre of Biotechnology, Laboratory of Proteolysis and Post-translational Modification of Proteins, Gronostajowa 7a, 30-387 Cracow, Poland. Electronic address: tomasz.kantyka@uj.edu.pl., Pyrc K; Jagiellonian University, Malopolska Centre of Biotechnology, Virogenetics, Laboratory of Virology, Gronostajowa 7a, 30-387 Cracow, Poland. Electronic address: k.a.pyrc@uj.edu.pl.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 May; Vol. 267 (Pt 1), pp. 131392. Date of Electronic Publication: 2024 Apr 04.
DOI: 10.1016/j.ijbiomac.2024.131392
Abstrakt: The main protease (M pro ) 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, M pro is a promising target for broad-spectrum antiviral drugs. Targeting M pro 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 M pro '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 M pro dimerization. We evaluated critical residues, specifically Arg4 and Arg298, that are essential for dimerization. Our results show that changes in the oligomerization state of M pro 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 M pro , offering promising new directions for therapeutic strategies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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