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Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Organic Chemistry.
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2011 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 9, no 15, 5445-5455 p.Article in journal (Refereed) Published
Abstract [en]

Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (K(a): 1560 +/- 20 M (1)). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested glycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design.

Place, publisher, year, edition, pages
2011. Vol. 9, no 15, 5445-5455 p.
Keyword [en]
MOLECULAR-DYNAMICS SIMULATIONS, FLEXIBLE LIGAND DOCKING, MISTLETOE LECTIN, CONFORMATIONAL-ANALYSIS, STRUCTURAL-CHANGES, HUMAN GALECTIN-3, SOLID-PHASE, CARBOHYDRATE-BINDING, CONFORMER SELECTION, ENDOGENOUS LECTINS
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Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-37280DOI: 10.1039/c0ob01235aISI: 000292983400020Scopus ID: 2-s2.0-79960370172OAI: oai:DiVA.org:kth-37280DiVA: diva2:433028
Note
QC 20110808Available from: 2011-08-08 Created: 2011-08-08 Last updated: 2017-12-08Bibliographically approved

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