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

Wang, Guan-Nan; André, Sabine; Gabius, Hans-Joachim and Murphy, Paul V. (2012): Bi- to tetravalent glycoclusters: synthesis, structure-activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity. In: Organic & Biomolecular Chemistry, Vol. 10, No. 34: pp. 6893-6907

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.

• Item Type: Journal article
• Form of publication: Publisher's Version
• Faculties: Veterinary Medicine
• Subjects: 500 Science > 540 Chemistry; 600 Technology > 610 Medicine and health
• ISSN: 1477-0520
• Alliance/National Licence: This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
• Language: English