Mimics of Ganglioside GM1 as Cholera Toxin Ligands: Replacement of the GalNAc Residue.

Abstract

Carbohydrates Carbohydrates U 0500 Mimics of Ganglioside GM1 as Cholera Toxin Ligands: Replacement of the GalNAc Residue. -(BERNARDI*, A.; AROSIO, D.; MANZONI, L.; MONTI, D.; POSTERI, H.; POTENZA, D.; MARI, S.; JIMENEZ-BARBERO, J.; Org. Biomol. Chem 1 (2003) 5, 785-792; Dip. Chim. Org. Ind., Univ. Stud. Milano, CNR, I-20133 Milano, Italy; Eng.) -S. Adam 26-213

Intramolecular Carbohydrate–Aromatic Interactions and Intermolecular van der Waals Interactions Enhance the Molecular Recognition Ability of GM1 Glycomimetics for Cholera Toxin

“…Regarding the orientation of the acetamide moiety [18] of both 6 and 7, the cross-peak of the methyl group with the corresponding H-2 GalNAc proton is a very weak, and no cross-peaks to either H-1 or H-3 GalNAc are observed. Therefore, these observations are in agreement with a major orientation in solution with the methyl group pointing out of the pyranoid ring with an anti-like relationship with the C-2 atom.…”

“…[8,18] In fact, only the very strong interresidue H-1 GalNAc/H-4 CHD cross-peak is observed; this cross-peak corresponds to a H-1 GalNAc/H-4 CHD distance of 2.5 AE 0.2 . The average conformation in solution for this linkage corresponds to the global minimum syn conformer, characterized by F/Y values of around 508/208.…”

“…The orientation around the Galb(1!3)GalNAc linkage can be defined [8,18] by the NOE contact observed between the anomeric proton of galactose, H-1 Gal, and the protons on the GalNAc moiety, especially H-3, H-4, and H-2. The H-1 Gal/H-3 GalNAc cross-peak is very strong for both 6 and 7 (see Tables 2 and 3), with an interaction similar to or even stronger than the corresponding intraresidue H-1 Gal/H-3 Gal and H-1 Gal/H-5 Gal crosspeaks.…”

Sialyloligosaccharides inhibit cholera toxin binding to the GM1 receptor

“…Since complex bioactive oligosaccharides are not often readily available, Bernardi et al have been producing multivalent displays of synthetically more accessible sugar mimics. 71 Using a pseudo-GM1 tetrasaccharide on a polyvalent 3,5-di-(2-aminoethoxy)benzoic acid branched scaffold, a highly active Ctx ligand was produced with inhibitory ELISA establishing this structure as a strong artificial monovalent Ctx binder, where >200 g mL À1 inhibited 100% of 1.75 g mL À1 Ctx-HRP. 72 Despite this success, such synthesised inhibitors are expensive and are not food grade molecules, and would therefore require extensive clinical trials in animal models before their consideration Figure 4.…”

Synthesis of L‐ and D‐4,6‐Dideoxyhexoses and 4,6‐Dideoxy‐C‐phenylglycosides from Enzyme‐Generated Products

“…The design of glycomimetic structures is aimed at reducing the carbohydrate-likeness of the mimics and to increase their drug-like properties. [14] Ganglioside GM1, for example, interacts with cholera toxin using galactose and N-acetylneuraminic acid residues at the oligosaccharide non-reducing end. [15] It was discovered that the terminal galactose could potentially serve as an "anchor" point for antagonist design, [16] and aryl galactosides [17] and galactose dendrimers [18] were developed as effective cholera toxin antagonists.…”