title: 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.
authors: School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
authors: Guan-Nan
authors: GN
authors: Wang
authors: Sabine
authors: S
authors: André
authors: Hans-Joachim
authors: HJ
authors: Gabius
authors: Paul V
authors: PV
authors: Murphy
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D060326:Chemistry Techniques, Synthetic; D002645:Chickens; D037161:Galectins / Q000037:antagonists & inhibitors; D006801:Humans; D037102:Lectins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D037121:Plant Lectins / Q000037:antagonists & inhibitors; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D037161:Galectins; D037102:Lectins; D037121:Plant Lectins; D011134:Polysaccharides