2. Academic Validation
  3. Methylcarvones as immunomodulators through antagonism of aryl hydrocarbon receptor

Methylcarvones as immunomodulators through antagonism of aryl hydrocarbon receptor

  • Bioorg Chem. 2025 Dec:167:109256. doi: 10.1016/j.bioorg.2025.109256.
Iveta Zůvalová 1,  Aneta Grycová 2,  Jiří Hrubý 2,  Peter Illés 2,  Miroslav Soural 3,  Ondřej Kováč 3,  Marek Šebela 4,  Petr Bachleda 5,  Eva Kriegová 6,  Markéta Trajerová 6,  Zdeněk Dvořák 7
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 779 00 Olomouc, Czech Republic. Electronic address: [email protected].
  • 2 Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 779 00 Olomouc, Czech Republic.
  • 3 Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46 Olomouc, Czech Republic.
  • 4 Department of Biochemistry, Faculty of Science, Palacký University, Šlechtitelů 27, 779 00 Olomouc, Czech Republic.
  • 5 Department of Cardiovascular and Transplantation Surgery, University Hospital Olomouc, Zdravotníků 7, 779 00 Olomouc, Czech Republic.
  • 6 Department of Immunology, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic.
  • 7 Department of Cell Biology and Genetics, Faculty of Science, Palacký University, Šlechtitelů 27, 779 00 Olomouc, Czech Republic. Electronic address: [email protected].
PMID: 41253061 DOI: 10.1016/j.bioorg.2025.109256
Abstract

Monocyclic monoterpenoids have been demonstrated as atypical negative allosteric modulators of Aryl Hydrocarbon Receptor AhR. The alkylation of the skeleton has been identified as a factor modulating the AhR antagonist activity of S-carvone. In the present study, we synthesized methylated derivatives of S-carvone, and a complex series of experimental approaches has been employed to characterize the interactions of novel compounds with AhR. Molecular docking to AhR carvone-binding site revealed binding energies for 6-methylated carvones superior to that of S-carvone. This prediction was corroborated by microscale thermophoresis, where 6-methylated carvones displayed stronger binding to AhR N-terminal region, as compared to S-carvone. Methylated carvones inhibited AhR transcriptional activity in vitro in cell lines, as revealed by reporter gene assay and RT-PCR. However, their effects were weaker than those predicted by molecular docking, which might be due to the transmembrane transport and metabolism. As a proof-of-concept, we show immunomodulatory effects of S-carvone and its methyl derivatives in the model of differentiated THP1 macrophages polarized into M1/M2 phenotypes.

Keywords

Allosteric binding; Aryl hydrocarbon receptor; Carvone; Immunomodulation.

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