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

• Published in: ChemMedChem 2010-03, Vol.5 (3), p.415-419
• Main Authors: Ribeiro, João P., André, Sabine, Cañada, F. Javier, Gabius, Hans-Joachim, Butera, Anna Paola, Alves, Ricardo José, Jiménez-Barbero, Jesús
• Format: Article
• Language: English
• Subjects: antitumor agents; Cell Line, Tumor; Cell Membrane - metabolism; Drug Design; Glycoproteins - metabolism; Humans; Lactose - chemistry; Lactose - pharmacology; lectins; Lectins - metabolism; Ligands; Models, Biological; molecular recognition; NMR; Nuclear Magnetic Resonance, Biomolecular; Plant Proteins - metabolism; Protein Binding; Ribosome Inactivating Proteins, Type 2 - metabolism; Toxins, Biological - metabolism; Viscum album - chemistry
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200900476

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 relevent to research into human lectins, glycosciences, and beyond. Carbohydrate chemistry: Sugar‐binding proteins, lectins, are an increasingly valid target in drug design with growing awareness of the biological importance of glycans. A series of modified lactosides containing aromatic aglycan moieties were tested in a plant toxin model for their ability to block lectin binding to cell‐surface glycans and consequently prevent the uptake of the plant toxin by the cell.