Preorganization of the Bioactive Conformation of Sialyl LewisX Analogues Correlates with Their Affinity to E-Selectin

Abstract

It pays to be organized: Steric repulsion between fucose and the methyl substituent of the adjacent tetrahydropyran reduces the distance between galactose and fucose in the E‐selectin antagonist 1 compared to the distance in closely related compounds that lack the methyl group. This effect causes a solution conformation of 1 that already resembles its conformation when bound to E‐selectin and, thus, leads to a significantly improved bioactivity.

From carbohydrate leads to glycomimetic drugs

“…Detailed insight into the binding event can be gained by nuclear magnetic resonance (nMR) experiments. For example, the bound conformation of a functional carbo hydrate ligand in the CRD of the target lectin can be deter mined using transferred nuclear Overhauser effect (nOE) 130 . In addition, the binding epitope can be identified by satu ration transfer difference nMR spectroscopy (STD NMR spectroscopy) 131 .…”

“…It was successfully replaced by noncarbohydrate link ers 141,142 . In addition, steric repulsion deriving from properly placed substituents on the linker moiety can further improve the preorganization of the core and, as a result, the affinity of the corresponding antagonist 130 . Furthermore, the preorganization of the carboxylate was optimized as well, revealing (S)cyclohexyl lactic acid as the best mimic of neu5Ac 141 .…”

“…In the bioactive conformation (complex 29), the core conformation is approximately -40° and an acid orientation is approximately 110° . The degree of pre-organization of a mimetic in the bioactive conformation, as shown in complex 30, can be correlated with its affinity 130,141 . b | Affinity can be improved by establishing new enthalpic interactions; comparisons of the binding mode of Neu5Ac2en (compound 31), zanamivir (Relenza) 7 and oseltamivir (Tamiflu) 9 to neuraminidase are depicted.…”

Shaping up for structural glycomics: a predictive protocol for oligosaccharide conformational analysis applied to N-linked glycans

“…At a 3D-molecular level, the closest interactions between sLe x and selectin active-site amino acids are to galactose and fucose 9 . Forcibly restricting the inter-ring distance between these monosaccharides by chemical methods has led to increasingly potent in vitro selectin inhibitors, highlighting their importance 13 . These two pyranose rings stack together, forming a compact secondary-structure in water and when protein bound, 14 and they have been assumed to be rigid chair-like puckers.…”

Chemoenzymatic Synthesis of Functional Sialyl LewisX Mimetics with a Heteroaromatic Core

“…These results demonstrate that functional sLe X mimetics can be obtained without any particular relative preorganization of the 3-sialylgalactose unit with the fucose moiety or a suitable substitute through an exo -anomeric effect. Substitution of the GlcNAc portion of sLe X , the impact of which on the overall conformation of the tetrasaccharide has been thoroughly investigated,[22] by two simple heteroarenes even leads to compounds with improved affinity for P- and/or L-selectin without the need to address distal binding pockets. [23] Although the metabolic stability of the as-prepared mimetics has not yet been tested, complete inertness of the two modified glycosidic bonds against degrading glycosidases is to be expected because the essential structural features for the action of these enzymes are missing.…”