title: Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition.
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.
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
authors.forename: Tamara
authors.initials: T
authors.lastname: Delaine
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia.
authors.forename: Patrick
authors.initials: P
authors.lastname: Collins
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: MacKinnon
authors.affiliation: Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Stegmayr
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
authors.forename: Vishal K
authors.initials: VK
authors.lastname: Rajput
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
authors.forename: Santanu
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
authors.forename: Ian
authors.initials: I
authors.lastname: Cumpstey
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
authors.forename: Amaia
authors.initials: A
authors.lastname: Larumbe
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.|Chemistry Department, The Hashemite University, P. O. Box 150459, Zarka, 13115, Jordan.
authors.forename: Bader A
authors.initials: BA
authors.lastname: Salameh
authors.affiliation: Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Kahl-Knutsson
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: van Hattum
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands.|Translational Metabolic Laboratory, 51 Radboud University Medical Center, P. O. Box 9101, 6500 HB, Nijmegen, Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van Scherpenzeel
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands.
authors.forename: Roland J
authors.initials: RJ
authors.lastname: Pieters
authors.affiliation: Department of Respiratory Medicine and Allergy, Kings College, 41 Denmark Hill Campus, Bessemer Road, London, SE5 9RJ, UK.
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
authors.affiliation: Galecto Biotech ApS, COBIS, Ole Maaloes vej 3, Copenhagen N, 2200, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Schambye
authors.affiliation: Department of Biology, Lund University, P. O. Box 118, 221 00, Lund, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Oredsson
authors.affiliation: Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
authors.forename: Hakon
authors.initials: H
authors.lastname: Leffler
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia. h.blanchard@griffith.edu.au.
authors.forename: Helen
authors.initials: H
authors.lastname: Blanchard
authors.affiliation: Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden. ulf.nilsson@chem.lu.se.
authors.forename: Ulf J
authors.initials: UJ
authors.lastname: Nilsson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001761:Bleomycin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D037502:Galectin 3 / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008968:Molecular Conformation; D011134:Polysaccharides / Q000032:analysis / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D013865:Thioglycosides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D037502:Galectin 3; D011134:Polysaccharides; D013865:Thioglycosides; D001761:Bleomycin
keywords: antagonists; fibrosis; galectins; inhibitors; thiodigalactosides; vesicles