From the ganglioside GQ1balpha to glycomimetic antagonists of the myelin-associated glycoprotein (MAG).
The tetrasaccharide 4, a substructure of ganglioside GQ1balpha, 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 Galbeta(1-3)GalNAc, as well as the terminal alpha(2-3)- and the internal alpha(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.
Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, Basel. beat.ernst@unibas.ch
Beat
B
Ernst
Oliver
O
Schwardt
Stefanie
S
Mesch
Matthias
M
Wittwer
Gianluca
G
Rossato
Angelo
A
Vedani
D000818:Animals; D016466:CHO Cells; D002240:Carbohydrate Sequence; D006224:Cricetinae; D003412:Cricetulus; D055808:Drug Discovery / Q000379:methods*; D004355:Drug Stability; D005732:Gangliosides / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000235:genetics; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
D005732:Gangliosides; D008024:Ligands; D018992:Myelin-Associated Glycoprotein; D009844:Oligosaccharides; C084317:GQ1balpha ganglioside