title: Lectin-based drug design: combined strategy to identify lead compounds using STD NMR spectroscopy, solid-phase assays and cell binding for a plant toxin model.
abstract: The growing awareness of the sugar code--i.e. the biological functionality of glycans--is leading to increased interest in lectins as drug targets. The aim of this study was to establish a strategic combination of screening procedures with increased biorelevance. As a model, we used a potent plant toxin (viscumin) and lactosides synthetically modified at the C6/C6' positions and the reducing end aglycan. Changes in the saturation transfer difference (STD) in NMR spectroscopy, applied in inhibition assays, yielded evidence for ligand activity and affinity differences. Inhibitory potency was confirmed by the blocking of lectin binding to a glycoprotein-bearing matrix. In cell-based assays, iodo/azido-substituted lactose derivatives were comparatively active. Interestingly, cell-type dependence was observed, indicating the potential of synthetic carbohydrate derivative to interact with lectins in a cell-type (glycan profile)-specific manner. These results are relevant to research into human lectins, glycosciences, and beyond.
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: João P
authors.initials: JP
authors.lastname: Ribeiro
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Cañada
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.forename: Anna Paola
authors.initials: AP
authors.lastname: Butera
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Alves
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007785:Lactose / Q000737:chemistry* / Q000494:pharmacology*; D037102:Lectins / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D019906:Nuclear Magnetic Resonance, Biomolecular; D010940:Plant Proteins / Q000378:metabolism*; D011485:Protein Binding; D054790:Ribosome Inactivating Proteins, Type 2 / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism*; D028182:Viscum album / Q000737:chemistry
chemical_list: D006023:Glycoproteins; D037102:Lectins; D008024:Ligands; D010940:Plant Proteins; D054790:Ribosome Inactivating Proteins, Type 2; D014118:Toxins, Biological; C488862:mistletoe lectin I; D007785:Lactose