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Andre, S,O'Sullivan, S,Gabius, HJ,Murphy, PV
2015
September
Tetrahedron
Glycoclusters as lectin inhibitors: comparative analysis on two plant agglutinins with different folding as a step towards rules for selectivity
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Glycoprotein Lectin Modelling N-Acetylglucosamine Valency WHEAT-GERM-AGGLUTININ ADHESION/GROWTH-REGULATORY GALECTINS MEDICALLY RELEVANT LECTINS CROSS-LINKING ACTIVITIES BANDEIRAEA-SIMPLICIFOLIA SEEDS N-ACETYLGLUCOSAMINE SUGAR CODE CARBOHYDRATE-BINDING TERMINAL ALKYNES IMMUNOGLOBULIN-G
71
6867
6880
The emerging physiological significance of carbohydrate (glycan) protein (lectin) recognition engenders the interest to design synthetic inhibitors with a high level of selectivity among natural sugar receptors. Plant agglutinins are common models to determine structure activity relationships. Focussing on the contribution of valency towards selectivity, copper-catalysed azide (sugar derivative)-alkyne (scaffold) cycloaddition yielded a panel of 10 bi- to tetravalent glycoclusters with N-acetylglucosamine as the bioactive headgroup. They were introduced into assays using (neo)glycoproteins and cell surfaces as platforms to study carbohydrate-dependent lectin binding. The ability of the bivalent compounds, which exhibit a distance profile of the sugar headgroups of about 16-21 angstrom, for intramolecular bridging of two contact sites from the eight hevein domains of wheat germ agglutinin led to comparatively high enhancements of inhibitory potency relative to a tetrameric leguminous lectin (distance profile of 50-70 angstrom between sugar-specific sites), especially for a beta-S-glycoside. The extent of inhibition at fixed concentrations of the sugar depended on the type of matrix used for the assay. Increases to tri- and tetravalency played a less important role than the anomeric position to keep cross-reactivity low, these tested topologies enabling cross-linking for both lectins. The potential for cis-interactions (intramolecular interactions), with glycoclusters serving as molecular rulers, is suggested to help designing selective blocking reagents. (C) 2015 Elsevier Ltd. All rights reserved.
10.1016/j.tet.2015.07.020
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