Galectin‐3‐Binding Glycomimetics that Strongly Reduce Bleomycin‐Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition |
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| Authors: | Dr Tamara Delaine Dr Patrick Collins Dr Alison MacKinnon Dr G Sharma John Stegmayr Dr Vishal K Rajput Dr Santanu Mandal Dr Ian Cumpstey Dr Amaia Larumbe Dr Bader A Salameh Barbro Kahl‐Knutsson Dr Hilde van?Hattum Dr Monique van?Scherpenzeel Prof Roland J Pieters Prof Tariq Sethi Dr Hans Schambye Prof Stina Oredsson Prof Hakon Leffler Assoc?Prof Helen Blanchard Prof Ulf J Nilsson |
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| Affiliation: | 1. Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Lund, Sweden;2. Institute for Glycomics, Griffith University, Queensland, Australia;3. MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK;4. Department of Laboratory Medicine, Section MIG, Lund University, Lund, Sweden;5. Chemistry Department, The Hashemite University, Zarka, Jordan;6. Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands;7. Translational Metabolic Laboratory, 51 Radboud University Medical Center, Nijmegen, Netherlands;8. Department of Respiratory Medicine and Allergy, Kings College, London, UK;9. Galecto Biotech ApS, COBIS, Copenhagen N, Denmark;10. Department of Biology, Lund University, Lund, Sweden |
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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 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 |
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