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  • Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition

    Author(s)
    Delaine, Tamara
    Collins, Patrick
    MacKinnon, Alison
    Sharma, G
    Stegmayr, John
    Rajput, Vishal K
    Mandal, Santanu
    Cumpstey, Ian
    Larumbe, Amaia
    Salameh, Bader A
    Kahl-Knutsson, Barbro
    van Hattum, Hilde
    van Scherpenzeel, Monique
    Pieters, Roland J
    Sethi, Tariq
    Schambye, Hans
    Oredsson, Stina
    Leffler, Hakon
    Blanchard, Helen
    Nilsson, Ulf J
    Griffith University Author(s)
    Collins, Patrick
    Blanchard, Helen
    Year published
    2016
    Metadata
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    Abstract
    Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3–glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3′-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive ...
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    Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3–glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3′-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin–carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
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    Journal Title
    ChemBioChem
    Volume
    17
    Issue
    18
    DOI
    https://doi.org/10.1002/cbic.201600285
    Subject
    Medicinal and biomolecular chemistry
    Medicinal and biomolecular chemistry not elsewhere classified
    Biochemistry and cell biology
    Publication URI
    http://hdl.handle.net/10072/100236
    Collection
    • Journal articles

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