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

Delaine, Tamara LU ; Collins, Patrick; Mackinnon, Alison; Sharma, G. LU ; Stegmayr, John LU ; Rajput, Vishal K.; Mandal, Santanu LU ; Cumpstey, Ian LU ; Larumbe, Amaia and Salameh, Bader A. LU , et al. (2016) In ChemBioChem
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,... (More)

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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publication status
epub
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keywords
Antagonists, Fibrosis, Galectins, Inhibitors, Thiodigalactosides, Vesicles
in
ChemBioChem
publisher
John Wiley & Sons
external identifiers
  • Scopus:84981347243
ISSN
1439-4227
DOI
10.1002/cbic.201600285
language
English
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yes
id
5113e975-ed77-4921-b323-f14d35030889
date added to LUP
2016-09-05 10:29:12
date last changed
2016-11-14 11:58:13
@misc{5113e975-ed77-4921-b323-f14d35030889,
  abstract     = {<p>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.</p>},
  author       = {Delaine, Tamara and Collins, Patrick and Mackinnon, Alison and Sharma, G. and Stegmayr, John and Rajput, Vishal K. and Mandal, Santanu and Cumpstey, Ian and Larumbe, Amaia and Salameh, Bader A. and Kahl Knutson, Barbro and vanHattum, Hilde and van Scherpenzeel, Monique and Pieters, Roland J. and Sethi, Tariq and Schambye, Hans and Oredsson, Stina and Leffler, Hakon and Blanchard, Helen and Nilsson, Ulf},
  issn         = {1439-4227},
  keyword      = {Antagonists,Fibrosis,Galectins,Inhibitors,Thiodigalactosides,Vesicles},
  language     = {eng},
  publisher    = {ARRAY(0xa3cb0f8)},
  series       = {ChemBioChem},
  title        = {Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition},
  url          = {http://dx.doi.org/10.1002/cbic.201600285},
  year         = {2016},
}