Modular Synthesis and Study of Multivalent Carbohydrate Ligands with Long and Flexible Linkers

Abstract

A unique feature of cell surface protein–carbohydrate interactions is that they are usually multivalent—meaning that there are multiple carbohydrates interacting with a single protein at multiple identical binding sites simultaneously. With this multivalent strategy, nature is building strong biological interactions by combining many weaker ones. Not surprisingly, synthetic ligands that mimic cell surface carbohydrates can also be made multivalent, which makes a synthetic ligand more effective in performing its intended task than the corresponding monovalent ligand. By taking into account the spatial arrangement of binding sites on a target protein, high-affinity multivalent ligands that geometrically complement their target can be designed and synthesized. The most advanced demonstrations of structure-based multivalent ligand designed to date are the development of pentavalent and decavalent carbohydrate inhibitors that are capable of blocking cell surface binding by AB 5 toxins. Among these, authors have developed a modular synthetic approach that allows rapid synthesis and optimization of large multivalent carbohydrate ligands using long and flexible linkers.