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High affinity sialoside ligands of myelin associated glycoprotein

Zeng, Y. and Rademacher, C. and Nycholat, C. M. and Futakawa, S. and Lemme, K. and Ernst, Beat and Paulson, J. C.. (2011) High affinity sialoside ligands of myelin associated glycoprotein. Bioorganic and Medicinal Chemistry Letters, 21 (17). pp. 5045-5049.

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Official URL: http://edoc.unibas.ch/46595/

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Abstract

Myelin associated glycoprotein (Siglec-4) is a myelin adhesion receptor, that is, well established for its role as an inhibitor of axonal outgrowth in nerve injury, mediated by binding to sialic acid containing ligands on the axonal membrane. Because disruption of myelin–ligand interactions promotes axon outgrowth, we have sought to develop potent ligand based inhibitors using natural ligands as scaffolds. Although natural ligands of MAG are glycolipids terminating in the sequence NeuAcα2–3Galβ1–3(±NeuAcα2−6)GalNAcβ-R, we previously established that synthetic O-linked glycoprotein glycans with the same sequence α-linked to Thr exhibited ∼1000-fold increased affinity (∼1 μM). Attempts to increase potency by introducing a benzoylamide substituent at C-9 of the α2–3 sialic acid afforded only a two-fold increase, instead of increases of >100-fold observed for other sialoside ligands of MAG. Surprisingly, however, introduction of a 9-N-fluoro-benzoyl substituent on the α2–6 sialic acid increased affinity 80-fold, resulting in a potent inhibitor with a Kd of 15 nM. Docking this ligand to a model of MAG based on known crystal structures of other siglecs suggests that the Thr positions the glycan such that aryl substitution of the α2–3 sialic acid produces a steric clash with the GalNAc, while attaching an aryl substituent to the other sialic acid positions the substituent near a hydrophobic pocket that accounts to the increase in affinity.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ernst)
UniBasel Contributors:Ernst, Beat and Lemme, Katrin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0960-894X
e-ISSN:1464-3405
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:30 Nov 2017 07:39
Deposited On:30 Nov 2017 07:39

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