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

Journal Article


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.

Publication Date


  • 2016

Citation


  • Rajput, V. K., MacKinnon, A., Mandal, S., Collins, P., Blanchard, H., Leffler, H., . . . Nilsson, U. J. (2016). A Selective Galactose-Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model. Journal of Medicinal Chemistry, 59(17), 8141-8147. doi:10.1021/acs.jmedchem.6b00957

Scopus Eid


  • 2-s2.0-84986579038

Start Page


  • 8141

End Page


  • 8147

Volume


  • 59

Issue


  • 17

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.

Publication Date


  • 2016

Citation


  • Rajput, V. K., MacKinnon, A., Mandal, S., Collins, P., Blanchard, H., Leffler, H., . . . Nilsson, U. J. (2016). A Selective Galactose-Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model. Journal of Medicinal Chemistry, 59(17), 8141-8147. doi:10.1021/acs.jmedchem.6b00957

Scopus Eid


  • 2-s2.0-84986579038

Start Page


  • 8141

End Page


  • 8147

Volume


  • 59

Issue


  • 17