Format

Send to

Choose Destination
Chembiochem. 2016 Sep 15;17(18):1759-70. doi: 10.1002/cbic.201600285. Epub 2016 Aug 12.

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

Author information

1
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden.
2
Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia.
3
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4TJ, UK.
4
Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
5
Chemistry Department, The Hashemite University, P. O. Box 150459, Zarka, 13115, Jordan.
6
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, Netherlands.
7
Translational Metabolic Laboratory, 51 Radboud University Medical Center, P. O. Box 9101, 6500 HB, Nijmegen, Netherlands.
8
Department of Respiratory Medicine and Allergy, Kings College, 41 Denmark Hill Campus, Bessemer Road, London, SE5 9RJ, UK.
9
Galecto Biotech ApS, COBIS, Ole Maaloes vej 3, Copenhagen N, 2200, Denmark.
10
Department of Biology, Lund University, P. O. Box 118, 221 00, Lund, Sweden.
11
Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland, 4222, Australia. h.blanchard@griffith.edu.au.
12
Centre for Analysis and Synthesis, Department of Chemistry, Lund University, P. O. Box 124, 221 00, Lund, Sweden. ulf.nilsson@chem.lu.se.

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.

KEYWORDS:

antagonists; fibrosis; galectins; inhibitors; thiodigalactosides; vesicles

PMID:
27356186
DOI:
10.1002/cbic.201600285
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center