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dc.contributor.authorDelaine, Tamara
dc.contributor.authorCollins, Patrick
dc.contributor.authorMacKinnon, Alison
dc.contributor.authorSharma, G
dc.contributor.authorStegmayr, John
dc.contributor.authorRajput, Vishal K
dc.contributor.authorMandal, Santanu
dc.contributor.authorCumpstey, Ian
dc.contributor.authorLarumbe, Amaia
dc.contributor.authorSalameh, Bader A
dc.contributor.authorKahl-Knutsson, Barbro
dc.contributor.authorvan Hattum, Hilde
dc.contributor.authorvan Scherpenzeel, Monique
dc.contributor.authorPieters, Roland J
dc.contributor.authorSethi, Tariq
dc.contributor.authorSchambye, Hans
dc.contributor.authorOredsson, Stina
dc.contributor.authorLeffler, Hakon
dc.contributor.authorBlanchard, Helen
dc.contributor.authorNilsson, Ulf J
dc.date.accessioned2017-11-27T04:42:25Z
dc.date.available2017-11-27T04:42:25Z
dc.date.issued2016
dc.identifier.issn1439-4227
dc.identifier.doi10.1002/cbic.201600285
dc.identifier.urihttp://hdl.handle.net/10072/100236
dc.description.abstractDiscovery 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherJohn Wiley & Sons
dc.relation.ispartofpagefrom1759
dc.relation.ispartofpageto1770
dc.relation.ispartofissue18
dc.relation.ispartofjournalChemBioChem
dc.relation.ispartofvolume17
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry not elsewhere classified
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchBiochemistry and Cell Biology
dc.subject.fieldofresearchcode030499
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0601
dc.titleGalectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.hasfulltextNo Full Text
gro.griffith.authorCollins, Patrick
gro.griffith.authorBlanchard, Helen


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