High affinity sialoside ligands of myelin associated glycoprotein

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Zeng, Ying¹  Rademacher, Christoph¹  Nycholat, Corwin M.¹  Futakawa, Satoshi¹  Lemme, Katrin²  Ernst, Beat²  Paulson, James C.¹ 

[1] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA

[2] Univ Basel, Inst Mol Pharm, CH-4056 Basel, Switzerland

关键词: Myelin associated glycoprotein;    MAG;    Siglec;    Sialic acid;    Lectin;   

DOI  :  10.1016/j.bmcl.2011.04.068

来源: Elsevier

【 摘 要 】

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 NeuAc alpha 2-3Gal beta 1-3(+/- NeuAc alpha 2-6) GalNAc beta-R, we previously established that synthetic O-linked glycoprotein glycans with the same sequence alpha-linked to Thr exhibited similar to 1000-fold increased affinity (similar to 1 mu M). Attempts to increase potency by introducing a benzoylamide substituent at C-9 of the alpha 2-3 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 alpha 2-6 sialic acid increased affinity 80-fold, resulting in a potent inhibitor with a K(d) 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 alpha 2-3 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. (C) 2011 Elsevier Ltd. All rights reserved.

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