Linear triazole-linked pseudo oligogalactosides as scaffolds for galectin inhibitor development.


Journal

Chemical biology & drug design
ISSN: 1747-0285
Titre abrégé: Chem Biol Drug Des
Pays: England
ID NLM: 101262549

Informations de publication

Date de publication:
10 2020
Historique:
received: 20 08 2019
revised: 10 01 2020
accepted: 14 03 2020
pubmed: 29 3 2020
medline: 8 7 2021
entrez: 29 3 2020
Statut: ppublish

Résumé

Galectins play key roles in numerous biological processes. Their mode of action depends on their localization which can be extracellular, cytoplasmic, or nuclear and is partly mediated through interactions with β-galactose containing glycans. Galectins have emerged as novel therapeutic targets notably for the treatment of inflammatory disorders and cancers. This has stimulated the design of carbohydrate-based inhibitors targeting the carbohydrate recognition domains (CRDs) of the galectins. Pursuing this approach, we reasoned that linear oligogalactosides obtained by straightforward iterative click chemistry could mimic poly-lactosamine motifs expressed at eukaryote cell surfaces which the extracellular form of galectin-3, a prominent member of the galectin family, specifically recognizes. Affinities toward galectin-3 consistently increased with the length of the representative oligogalactosides but without reaching that of oligo-lactosamines. Elucidation of the X-ray crystal structures of the galectin-3 CRD in complex with a synthesized di- and tri-galactoside confirmed that the compounds bind within the carbohydrate-binding site. The atomic structures revealed that binding interactions mainly occur with the galactose moiety at the non-reducing end, primarily with subsites C and D of the CRD, differing from oligo-lactosamine which bind more consistently across the whole groove formed by the five subsites (A-E) of the galectin-3 CRD.

Identifiants

pubmed: 32220037
doi: 10.1111/cbdd.13683
doi:

Substances chimiques

Biopolymers 0
Galactosides 0
Galectins 0
Triazoles 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1123-1133

Informations de copyright

© 2020 John Wiley & Sons A/S.

Références

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Auteurs

Christophe Dussouy (C)

Unité Fonctionnalité et Ingénierie des Protéines (UFIP), CNRS, UMR 6286, Université de Nantes, Nantes, France.

Chandan Kishor (C)

Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.

Annie Lambert (A)

Unité Fonctionnalité et Ingénierie des Protéines (UFIP), CNRS, UMR 6286, Université de Nantes, Nantes, France.

Clément Lamoureux (C)

Unité Fonctionnalité et Ingénierie des Protéines (UFIP), CNRS, UMR 6286, Université de Nantes, Nantes, France.

Helen Blanchard (H)

Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, NSW, Australia.

Cyrille Grandjean (C)

Unité Fonctionnalité et Ingénierie des Protéines (UFIP), CNRS, UMR 6286, Université de Nantes, Nantes, France.

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