Interfering with the Sugar Code: Design and Synthesis of Oligosaccharide Mimics

Abstract

Oligosaccharide determinants of cellular glycoconjugates interact with protein receptors triggering a variety of cellular responses within a wide range of physiological and pathological processes and with exquisitely tuned selectivity. This has led to the formulation of the hypothesis that a sugar code exists and that sugar-binding proteins (lectins) act to decipher it and translate it into biological responses. Interference with these recognition events by functional mimics of carbohydrates could thus be used to modulate or alter signal transmission, or to prevent the onset of diseases. Attempts to design and prepare glycomimetic inhibitors of well-known target lectins (cholera toxin, DC-SIGN) are reviewed in this concept paper.

Towards new cholera prophylactics and treatment: Crystal structures of bacterial enterotoxins in complex with GM1 mimics

“…GM1 mimics have the potential to overcome this problem, and to result in materials that are relatively inexpensive and sufficiently active. Various approaches have been adopted to mimic GM1-os 43–45 . In particular, searching for non-hydrolyzable analogs, we explored both simple C -galactosides (Fig.…”

“…An IC 50 of 125 μM was measured for 1 in SPR competition experiments inhibiting CTB binding to immobilized asialofetuin 45 . The affinity of 2 and 3 for CTB was evaluated as 0.8–1.2 mM by weak affinity chromatography (WAC) 43 . For comparison, the affinity of the reference MNPG in the same experiment was 1.3 mM.…”

A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus

“…This observation has turned DC-SIGN into an interesting target for the design of anti-viral agents. [2][3][4][5][6][7][8][9][10] The task is complicated by the presence of other C-type lectins of similar selectivity, like Langerin, [11] that has a protective effect against HIV infection. Thus, selective DC-SIGN ligands that interact only weakly with Langerin are actively sought after as potentially useful therapeutic tools against HIV and other viruses that use DC-SIGN as a primary receptor.…”

“…For this reason the principle of multivalency has been used with success in the development of antagonists of DC-SIGN and numerous reports have appeared in the literature concerning mannosylated dendrimers or polymers that target it. [8,10,[18][19][20][21][22] Multivalent structures bearing sugar mimics were previously prepared in our group [10,18] using Boltorn type dendrimers and dendrons derived from 2,2-bis(hydroxymethyl) propionic acid. These scaffolds have a polyester backbone of good flexibility and water solubility, and their outer layers are functionalized with carboxylic groups.…”

Enhanced Inhibition of Protein Carbohydrate Interactions by Dendritic Multivalent Glycoligands

“…The multivalency effect was able to overcome the many orders of magnitude lost in going from GM1os to the weakly binding galactoside monovalent ligand. Besides the multivalency approach a structure-based approach of optimizing monovalent ligands has also been ongoing (23). Recently such an improvement strategy was combined with the attachment of the newly built ligands to a multivalent polymeric backbone such as dextran (24).…”