Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition
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.
(2016) ChemBioChem, volume 17, issue 18, pp. 1759 - 1770
(Article)
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
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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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Keywords: Antagonists, Fibrosis, Galectins, Inhibitors, Thiodigalactosides, Vesicles, Taverne, Biochemistry, General Medicine, Molecular Medicine, Molecular Biology, Organic Chemistry
ISSN: 1439-4227
Publisher: Wiley-VCH Verlag
(Peer reviewed)
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