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

Research output: Contribution to journalArticle

Tamara Delaine, Patrick Collins, Alison MacKinnon, G. Sharma, John Stegmayr, Vishal K. Rajput, Santanu Mandal, Ian Cumpstey, Amaia Larumbe, Bader A. Salameh, Barbro Kahl-Knutsson, Hilde van Hattum, Monique van Scherpenzeel, Roland J. Pieters, Tariq Sethi, Hans Schambye, Stina Oredsson, Hakon Leffler, Helen Blanchard, Ulf J. Nilsson

Original languageEnglish
Pages (from-to)1759-1770
Number of pages12
JournalChembiochem : a European journal of chemical biology
Issue number18
Early online date12 Aug 2016
E-pub ahead of print12 Aug 2016
Published15 Sep 2016

King's Authors


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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