From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

Abstract

The tetrasaccharide 4, a substructure of ganglioside GQ1b?, 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 4, antagonists with modifications of the core disaccharide Gal?(1-3)GalNAc, as well as the terminal ?(2-3)- and the internal ?(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17.

Keywords

• Docking
• Hapten inhibition assay
• Homology model
• Gangliosides
• Myelin-associated glycoprotein (mag)
• Mag antagonists