Examination of the Biological Role of the α(2→6)-Linked Sialic Acid in Gangliosides Binding to the Myelin-Associated Glycoprotein (MAG)

• Published in: Journal of medicinal chemistry 2009-02, Vol.52 (4), p.989-1004
• Main Authors: Schwardt, Oliver, Gäthje, Heiko, Vedani, Angelo, Mesch, Stefanie, Gao, Gan-Pan, Spreafico, Morena, von Orelli, Johannes, Kelm, Sørge, Ernst, Beat
• Format: Article
• Language: English
• Subjects: Animals; Axons - physiology; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Gangliosides - metabolism; Medical sciences; Miscellaneous; Molecular Mimicry; Myelin-Associated Glycoprotein - antagonists & inhibitors; Myelin-Associated Glycoprotein - metabolism; N-Acetylneuraminic Acid - metabolism; Nerve Regeneration; Neuropharmacology; Pharmacology. Drug treatments; Protein Binding
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801058n

The tetrasaccharide 1, a substructure of ganglioside GQ1bα, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 1, modifications of the core disaccharide, the α(2→3)- and the α(2→6)-linked sialic acid were synthesized. Biphenylmethyl and (S)-lactate were identified as suitable replacements for the α(2→6)-linked sialic acid. Combined with a core modification and the earlier found aryl amide substituent in the 9-position of the α(2→3)-linked sialic acid, high affinity MAG antagonists were identified. All mimics were tested in a competitive target-based binding assay, providing relative inhibitory potencies (rIP). Compared to the reference tetrasaccharide 1, the rIPs of the most potent antagonists 59 and 60 are enhanced nearly 400-fold. Their K Ds determined in surface plasmon resonance experiments are in the low micromolar range. These results are in semiquantitative agreement with molecular modeling studies. This new class of glycomimetics will allow to validate the role of MAG in the axon regeneration process.