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

  • Tamara Delaine
  • Patrick Collins
  • Alison Mackinnon
  • G. Sharma
  • John Stegmayr
  • Vishal K. Rajput
  • Santanu Mandal
  • Ian Cumpstey
  • Amaia Larumbe
  • Bader A. Salameh
  • Barbro Kahl Knutson
  • Hilde vanHattum
  • Monique van Scherpenzeel
  • Roland J. Pieters
  • Tariq Sethi
  • Hans Schambye
  • Stina Oredsson
  • Hakon Leffler
  • Helen Blanchard
  • Ulf Nilsson
Publishing year: 2016
Language: English
Pages: 1759-1770
Publication/Series: ChemBioChem
Volume: 17
Issue: 18
Document type: Journal article
Publisher: John Wiley and Sons Ltd

Abstract english

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.


  • Medicinal Chemistry
  • Antagonists
  • Fibrosis
  • Galectins
  • Inhibitors
  • Thiodigalactosides
  • Vesicles


  • ISSN: 1439-4227
Stina Oredsson
E-mail: stina [dot] oredsson [at] biol [dot] lu [dot] se


Functional zoology

+46 46 222 94 97



Principal investigator

LUCC - Lund University Cancer Centre

Research group

Animal Physiology


Cell proliferation

Doctoral students and postdocs

PhD Students, main supervisor

Wendy Soria Sotillo

PhD Students, assistant supervisor

Atena Malakpour Permlid