Issue 34, 2012

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

Abstract

The emerging functional versatility of cellular glycans makes research on the design of synthetic inhibitors a timely topic. In detail, the combination of ligand (or headgroup or contact site) structure with spatial parameters that depend on topological and geometrical factors underlies the physiological selectivity of glycan-protein (lectin) recognition. We herein tested a panel of bi-, tri- and tetravalent compounds against two plant agglutinins and adhesion/growth-regulatory lectins (galectins). In addition, we examined the impact of headgroup tailoring (converting lactose to 2′-fucosyllactose) in combination with valency increase in two assay types of increasing biorelevance (from solid-phase binding to cell binding). Compounds were prepared using copper-catalysed azide alkyne cycloaddition from peracetylated lactosyl or 2′-fucosyllactosyl azides. Significant inhibition was achieved for the plant toxin with a tetravalent compound. Different levels of sensitivity were noted for the three groups of the galectin family. The headgroup extension to 2′-fucosyllactose led to a selectivity gain, especially for the chimera-type galectin-3. Valency increase established discrimination against the homodimeric proteins, whereas the combination of valency with the headgroup extension led to discrimination against the tandem-repeat-type galectin-8 for chicken galectins but not human galectins-3 and -4. Thus, detailed structure–activity profiling of glycoclusters combined with suitably modifying the contact site for the targeted lectin will help minimize cross-reactivity among this class of closely related proteins.

Graphical abstract: Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

Supplementary files

Article information

Article type
Paper
Submitted
07 May 2012
Accepted
27 Jun 2012
First published
29 Jun 2012

Org. Biomol. Chem., 2012,10, 6893-6907

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

G. Wang, S. André, H. Gabius and P. V. Murphy, Org. Biomol. Chem., 2012, 10, 6893 DOI: 10.1039/C2OB25870F

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