Probing the carbohydrate recognition domain of E-selectin: The importance of the acid orientation in sLex mimetics

被引：13

作者：

Titz, Alexander ^{[1
]}

Patton, John ^{[2
]}

Smiesko, Martin ^{[1
]}

Radic, Zorana ^{[1
]}

Schwardt, Oliver ^{[1
]}

Magnani, John L. ^{[2
]}

Ernst, Beat ^{[1
]}

机构：

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

[2] GlycoMimet Inc, Gaithersburg, MD 20878 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 01期

基金：

瑞士国家科学基金会;

关键词：

E-selectin; Sialyl Lewis(x); Pre-organization; Antagonist; Neu5Ac replacement; LEWIS-X EPITOPE; SIALYL LEWIS(X); CELL-ADHESION; BIOACTIVE CONFORMATION; CLICK CHEMISTRY; LIGANDS; ANTAGONISTS; PROTEINS; DESIGN; ELAM-1;

D O I：

10.1016/j.bmc.2009.11.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The selectin-leukocyte interaction is the initial event in the early inflammatory cascade. This interplay proceeds via the terminal tetrasaccharide sialyl Lewis(x) (sLe(x)), present on physiological selectin ligands and E- and P-selectins located on the endothelial surface. Blocking this process is regarded as a promising therapeutic approach for inflammatory diseases where excessive leukocyte efflux is responsible for tissue damage. Selectin antagonists are generally based on sLe(x) as lead structure, containing the essential pharmacophores pre-oriented in the bioactive conformation. In this work, we describe a set of competitive sLe(x) mimetics possessing the carboxylic acid pharmacophore equipped with additional hydrophobic substituents as neuraminic acid (Neu5Ac) replacements. This small library of antagonists derived from Huisgen-1,3-dipolar cycloadditions allows to further probe the carbohydrate recognition domain of E-selectin. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：19 / 27

页数：9

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