From the Ganglioside GQ1bα to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

Authors

  • Beat Ernst Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel;, Email: beat.ernst@unibas.ch
  • Oliver Schwardt Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel
  • Stefanie Mesch Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel
  • Matthias Wittwer Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel
  • Gianluca Rossato Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel
  • Angelo Vedani Institut für Molekulare Pharmazie, Pharmazentrum der Universität Basel, Klingelbergstrasse 50, CH-4056 Basel

DOI:

https://doi.org/10.2533/chimia.2010.17

Keywords:

Docking, Hapten inhibition assay, Homology model, Gangliosides, Myelin-associated glycoprotein (mag), Mag antagonists, Surface plasmon resonance (biacore)

Abstract

The tetrasaccharide 4, a substructure of ganglioside GQ1bα, shows a remarkable affinity for the myelinassociated 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 Galβ(1-3)GalNAc, as well as the terminal α(2-3)- and the internal α(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.

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Published

2010-02-26

How to Cite

[1]
B. Ernst, O. Schwardt, S. Mesch, M. Wittwer, G. Rossato, A. Vedani, Chimia 2010, 64, 17, DOI: 10.2533/chimia.2010.17.