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

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

doi:10.1021/acs.jmedchem.6b00957

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

65 Citations (Scopus)

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.

Original language	English
Pages (from-to)	8141-8147
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	17
Early online date	8 Aug 2016
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00957
Publication status	Published - 8 Sept 2016

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Rajput, V. K., MacKinnon, A., Mandal, S., Collins, P., Blanchard, H., Leffler, H., Sethi, T., Schambye, H., Mukhopadhyay, B., & 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. https://doi.org/10.1021/acs.jmedchem.6b00957

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

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.",

author = "Rajput, {Vishal K.} and Alison MacKinnon and Santanu Mandal and Patrick Collins and Helen Blanchard and Hakon Leffler and Tariq Sethi and Hans Schambye and Balaram Mukhopadhyay and Nilsson, {Ulf J.}",

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Rajput, VK, MacKinnon, A, Mandal, S, Collins, P, Blanchard, H, Leffler, H, Sethi, T, Schambye, H, Mukhopadhyay, B & Nilsson, UJ 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, vol. 59, no. 17, pp. 8141-8147. https://doi.org/10.1021/acs.jmedchem.6b00957

TY - JOUR

T1 - A Selective Galactose-Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model

AU - Rajput, Vishal K.

AU - MacKinnon, Alison

AU - Mandal, Santanu

AU - Collins, Patrick

AU - Blanchard, Helen

AU - Leffler, Hakon

AU - Sethi, Tariq

AU - Schambye, Hans

AU - Mukhopadhyay, Balaram

AU - Nilsson, Ulf J.

PY - 2016/9/8

Y1 - 2016/9/8

N2 - 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.

AB - 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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U2 - 10.1021/acs.jmedchem.6b00957

DO - 10.1021/acs.jmedchem.6b00957

M3 - Article

AN - SCOPUS:84986579038

SN - 0022-2623

VL - 59

SP - 8141

EP - 8147

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 17

ER -

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

Abstract

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