Investigation into the feasibility of thioditaloside as a novel scaffold for galectin-3-specific inhibitors.

Abstract

Galectin-3 is extensively involved in metabolic and disease processes, such as cancer metastasis, thus giving impetus for the design of specific inhibitors targeting this β-galactose-binding protein. Thiodigalactoside (TDG) presents a scaffold for construction of galectin inhibitors, and its inhibition of galectin-1 has already demonstrated beneficial effects as an adjuvant with vaccine immunotherapy, thereby improving the survival outcome of tumour-challenged mice. A novel approach--replacing galactose with its C2 epimer, talose--offers an alternative framework, as extensions at C2 permit exploitation of a galectin-3-specific binding groove, thereby facilitating the design of selective inhibitors. We report the synthesis of thioditaloside (TDT) and crystal structures of the galectin-3 carbohydrate recognition domain in complexes with TDT and TDG. The different abilities of galactose and talose to anchor to the protein correlate with molecular dynamics studies, likely explaining the relative disaccharide binding affinities. The feasibility of a TDT scaffold to enable access to a particular galectin-3 binding groove and the need for modifications to optimise such a scaffold for use in the design of potent and selective inhibitors are assessed.

• Authors: Khuchtumur Bum-Erdene, Ivan A Gagarinov, Patrick M Collins, Moritz Winger, Andrew G Pearson, Jennifer C Wilson, Hakon Leffler, Ulf J Nilsson, I Darren Grice, Helen Blanchard
• Journal: Chembiochem : a European journal of chemical biology (Chembiochem) Vol. 14 Issue 11 Pg. 1331-42 (Jul 22 2013) ISSN: 1439-7633 [Electronic] Germany
• PMID: 23864426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Disaccharides
• Galectin 3
• Thiogalactosides
• Thioglycosides
• thiodigalactoside

Topics

• Binding Sites
• Crystallography, X-Ray
• Disaccharides (chemical synthesis, chemistry, metabolism)
• Galectin 3 (antagonists & inhibitors, metabolism)
• Humans
• Hydrogen Bonding
• Protein Structure, Tertiary
• Static Electricity
• Thermodynamics
• Thiogalactosides (chemical synthesis, chemistry, metabolism)
• Thioglycosides (chemical synthesis, chemistry, metabolism)