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Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors

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Author

  • Khuchtumur Bum-Erdene
  • Ivan A. Gagarinov
  • Patrick M. Collins
  • Moritz Winger
  • Andrew G. Pearson
  • Jennifer C. Wilson
  • Hakon Leffler
  • Ulf Nilsson
  • I. Darren Grice
  • Helen Blanchard

Summary, in English

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 -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 approachreplacing galactose with its C2 epimer, taloseoffers 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.

Department/s

Publishing year

2013

Language

English

Pages

1331-1342

Publication/Series

ChemBioChem

Volume

14

Issue

11

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Immunology in the medical area
  • Microbiology in the medical area

Keywords

  • carbohydrates
  • chemical synthesis (thioditaloside)
  • inhibitors
  • molecular dynamics
  • protein structures

Status

Published

ISBN/ISSN/Other

  • ISSN: 1439-4227