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

Journal Article


Abstract


  • 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.

UOW Authors


  •   Blanchard, Helen (external author)

Publication Date


  • 2020

Citation


  • Dussouy, C., Kishor, C., Lambert, A., Lamoureux, C., Blanchard, H., & Grandjean, C. (2020). Linear triazole-linked pseudo oligogalactosides as scaffolds for galectin inhibitor development. Chemical Biology and Drug Design, 96(4), 1123-1133. doi:10.1111/cbdd.13683

Scopus Eid


  • 2-s2.0-85084986051

Start Page


  • 1123

End Page


  • 1133

Volume


  • 96

Issue


  • 4

Abstract


  • 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.

UOW Authors


  •   Blanchard, Helen (external author)

Publication Date


  • 2020

Citation


  • Dussouy, C., Kishor, C., Lambert, A., Lamoureux, C., Blanchard, H., & Grandjean, C. (2020). Linear triazole-linked pseudo oligogalactosides as scaffolds for galectin inhibitor development. Chemical Biology and Drug Design, 96(4), 1123-1133. doi:10.1111/cbdd.13683

Scopus Eid


  • 2-s2.0-85084986051

Start Page


  • 1123

End Page


  • 1133

Volume


  • 96

Issue


  • 4