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Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient
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SYSNO ASEP 0585278 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Glycomimetic inhibitors of tandem-repeat galectins: Simple and efficient Author(s) Vrbata, David (MBU-M) ORCID
Červený, Jakub (MBU-M) ORCID, RID
Kulik, Natalia (MBU-M) ORCID
Hovorková, Michaela (MBU-M)
Balogová, Soňa (MBU-M)
Vlachová, Miluše (MBU-M) ORCID
Pelantová, Helena (MBU-M) ORCID, RID
Křen, Vladimír (MBU-M) RID, ORCID
Bojarová, Pavla (MBU-M) ORCIDArticle number 107231 Source Title Bioorganic Chemistry. - : Elsevier - ISSN 0045-2068
Roč. 145, April 24 (2024)Number of pages 13 s. Language eng - English Country NL - Netherlands 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 R&D Projects GA22-00262S GA ČR - Czech Science Foundation (CSF) LUC23148 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure e-INFRA CZ II - 90254 - CESNET, zájmové sdružení právnických osob Method of publishing Limited access Institutional support MBU-M - RVO:61388971 UT WOS 001197668500001 EID SCOPUS 85186065776 DOI 10.1016/j.bioorg.2024.107231 Annotation 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2025 Electronic address https://www.sciencedirect.com/science/article/pii/S0045206824001366?via%3Dihub
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