Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient

0585278 - MBÚ 2025 RIV NL eng J - Journal Article
Vrbata, David - Červený, Jakub - Kulik, Natalia - Hovorková, Michaela - Balogová, Soňa - Vlachová, Miluše - Pelantová, Helena - Křen, Vladimír - Bojarová, Pavla
Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient.
Bioorganic Chemistry. Roč. 145, April 24 (2024), č. článku 107231. ISSN 0045-2068. E-ISSN 1090-2120
R&D Projects: GA ČR(CZ) GA22-00262S; GA MŠMT(CZ) LUC23148
Research Infrastructure: e-INFRA CZ II - 90254
Institutional support: RVO:61388971
Keywords : carbohydrate-recognition * domain * lectin * oligosaccharide * optimization * expression * crystal * docking * Glycomimetic * Molecular modeling * Tandem-repeat galectin * Structure-affinity relationship * Thiodigalactoside
OECD category: Biochemistry and molecular biology
Impact factor: 5.1, year: 2022
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/pii/S0045206824001366?via%3Dihub

The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3-O-disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9. The straightforward synthesis of these glycomimetics involved dibutyltin oxide-catalyzed 3,3-O-disubstitution of commercially available unprotected thiodigalactoside, and conjugation of various aryl substituents by copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC). The inhibitory potential of the prepared glycomimetics for Gal-8 and Gal-9 was assessed, and compared with the established galectins Gal-1 and Gal-3. The introduction of C-3 substituents resulted in an over 40-fold increase in affinity compared with unmodified TDG. The structure-affinity relations within the studied series were discussed using molecular modeling. Furthermore, the prepared glycomimetics were shown to scavenge Gal-8 and Gal-9 from the surface of cancer cells. This pioneering study on the synthetic inhibitors especially of Gal-9 identified lead compounds that may be used in further biomedical research.
Permanent Link: https://hdl.handle.net/11104/0353049