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J Med Chem. 2016 Sep 8;59(17):8141-7. doi: 10.1021/acs.jmedchem.6b00957. Epub 2016 Aug 23.

A Selective Galactose-Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model.

Author information

1
Indian Institute of Science Education and Research-Kolkata (IISER) Kolkata , Mohanpur Campus, P.O. BCKV Campus Main Office, Mohanpur, Nadia 741246, India.
2
Centre for Analysis and Synthesis, Department of Chemistry, Lund University , POB 124, SE-221 00 Lund, Sweden.
3
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh , Edinburgh EH16 4TJ, U.K.
4
Institute for Glycomics, Griffith University , Gold Coast Campus, Parklands Southport, Queensland 4222, Australia.
5
Department of Laboratory Medicine, Section MIG, Lund University , BMC-C1228b, Klinikgatan 28, SE-221 84 Lund, Sweden.
6
Department of Respiratory Medicine and Allergy, Kings College , Denmark Hill Campus, Bessemer Road, London SE5 9RS, U.K.
7
Galecto Biotech ApS, COBIS , Ole Maaloes vej 3, Copenhagen N, DK-2200, Denmark.

Abstract

Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3-O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target.

PMID:
27500311
DOI:
10.1021/acs.jmedchem.6b00957
[Indexed for MEDLINE]

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