Prev. Article Next Article Table of Contents

Article

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

Your current credentials do not allow retrieval of the full text.

Purchase the full-text

PDF/HTML,
figures/images,
references and tables,
(where available)

Oliver Schwardt^†, Heiko Gäthje^‡, Angelo Vedani^†, Stefanie Mesch^†, Gan-Pan Gao^†, Morena Spreafico^†, Johannes von Orelli^†, Sørge Kelm^‡ and Beat Ernst*^†

Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland, Institute for Physiological Biochemistry, University Bremen, D-28334 Bremen, Germany

J. Med. Chem., 2009, 52 (4), pp 989–1004

DOI: 10.1021/jm801058n

Publication Date (Web): January 28, 2009

* To whom correspondence should be addressed. Phone: 0041 267 15 51. Fax: 0041 267 15 52. E-mail: beat.ernst@unibas.ch., †

Institute of Molecular Pharmacy, Pharmacenter, University of Basel.

, ‡

Institute for Physiological Biochemistry, University Bremen.

Section:

General Biochemistry

Abstract

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.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Citing Articles

Citation data is made available by participants in CrossRef's Cited-by Linking service. For a more comprehensive list of citations to this article, users are encouraged to perform a search in SciFinder.

This article has been cited by 1 ACS Journal articles (1 most recent appear below).

Low Molecular Weight Antagonists of the Myelin-Associated Glycoprotein: Synthesis, Docking, and Biological Evaluation
Stefanie Mesch, Delia Moser, Daniel S. Strasser, Antje Kelm, Brian Cutting, Gianluca Rossato, Angelo Vedani, Hendrik Koliwer-Brandl, Matthias Wittwer, Said Rabbani, Oliver Schwardt, Soerge Kelm and Beat Ernst
Journal of Medicinal Chemistry2010 53 (4), 1597-1615
- Low Molecular Weight Antagonists of the Myelin-Associated Glycoprotein: Synthesis, Docking, and Biological Evaluation
  Stefanie Mesch, Delia Moser, Daniel S. Strasser, Antje Kelm, Brian Cutting, Gianluca Rossato, Angelo Vedani, Hendrik Koliwer-Brandl, Matthias Wittwer, Said Rabbani, Oliver Schwardt, Soerge Kelm and Beat Ernst
  Journal of Medicinal Chemistry2010 53 (4), 1597-1615
  The injured adult mammalian central nervous system is an inhibitory environment for axon regeneration due to specific inhibitors, among them the myelin-associated glycoprotein (MAG), a member of the Siglec family (sialic-acid binding immunoglobulin-like ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links