title: Examination of the biological role of the alpha(2-->6)-linked sialic acid in gangliosides binding to the myelin-associated glycoprotein (MAG).
abstract: The tetrasaccharide 1, a substructure of ganglioside GQ1b alpha, 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 alpha(2-->3)- and the alpha(2-->6)-linked sialic acid were synthesized. Biphenylmethyl and (S)-lactate were identified as suitable replacements for the alpha(2-->6)-linked sialic acid. Combined with a core modification and the earlier found aryl amide substituent in the 9-position of the alpha(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(D)s 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.
authors.affiliation: Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Schwardt
authors.forename: Heiko
authors.initials: H
authors.lastname: Gäthje
authors.forename: Angelo
authors.initials: A
authors.lastname: Vedani
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mesch
authors.forename: Gan-Pan
authors.initials: GP
authors.lastname: Gao
authors.forename: Morena
authors.initials: M
authors.lastname: Spreafico
authors.forename: Johannes
authors.initials: J
authors.lastname: von Orelli
authors.forename: Sørge
authors.initials: S
authors.lastname: Kelm
authors.forename: Beat
authors.initials: B
authors.lastname: Ernst
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005732:Gangliosides / Q000378:metabolism*; D018716:Molecular Mimicry; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D009416:Nerve Regeneration; D011485:Protein Binding
chemical_list: D005732:Gangliosides; D018992:Myelin-Associated Glycoprotein; D019158:N-Acetylneuraminic Acid