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

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Rajput, Vishal K
MacKinnon, Alison
Mandal, Santanu
Collins, Patrick
Blanchard, Helen
Leffler, Hakon
Sethi, Tariq
Schambye, Hans
Mukhopadhyay, Balaram
Nilsson, Ulf J
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2016
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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.

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Journal of Medicinal Chemistry

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59

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Medicinal and biomolecular chemistry

Medicinal and biomolecular chemistry not elsewhere classified

Organic chemistry

Pharmacology and pharmaceutical sciences

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