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

Bum-Erdene, Khuchtumur; Gagarinov, Ivan A.; Collins, Patrick M.; Winger, Moritz; Pearson, Andrew G.; Wilson, Jennifer C.; Leffler, Hakon LU ; Nilsson, Ulf LU ; Grice, I. Darren and Blanchard, Helen (2013) In ChemBioChem 14(11). p.1331-1342
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 -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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
carbohydrates, chemical synthesis (thioditaloside), inhibitors, molecular dynamics, protein structures
in
ChemBioChem
volume
14
issue
11
pages
1331 - 1342
publisher
John Wiley & Sons
external identifiers
  • wos:000321895800013
  • scopus:84880623416
ISSN
1439-4227
DOI
10.1002/cbic.201300245
language
English
LU publication?
yes
id
273526da-7d0a-4a41-9557-460c397eea6f (old id 3973361)
date added to LUP
2013-08-27 15:50:34
date last changed
2019-01-06 04:42:18
@article{273526da-7d0a-4a41-9557-460c397eea6f,
  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 -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.},
  author       = {Bum-Erdene, Khuchtumur and Gagarinov, Ivan A. and Collins, Patrick M. and Winger, Moritz and Pearson, Andrew G. and Wilson, Jennifer C. and Leffler, Hakon and Nilsson, Ulf and Grice, I. Darren and Blanchard, Helen},
  issn         = {1439-4227},
  keyword      = {carbohydrates,chemical synthesis (thioditaloside),inhibitors,molecular dynamics,protein structures},
  language     = {eng},
  number       = {11},
  pages        = {1331--1342},
  publisher    = {John Wiley & Sons},
  series       = {ChemBioChem},
  title        = {Investigation into the Feasibility of Thioditaloside as a Novel Scaffold for Galectin-3-Specific Inhibitors},
  url          = {http://dx.doi.org/10.1002/cbic.201300245},
  volume       = {14},
  year         = {2013},
}