Lectin-mediated drug targeting:: Selection of valency, sugar type (Gal/Lac), and spacer length for cluster glycosides as parameters to distinguish ligand binding to C-type asialoglycoprotein receptors and galectins
Lectin-mediated drug targeting:: Selection of valency, sugar type (Gal/Lac), and spacer length for cluster glycosides as parameters to distinguish ligand binding to C-type asialoglycoprotein receptors and galectins
复制标题
DOI：
10.1023/a:1007535506705
复制
发表时间：
2000-08-01
影响因子：
3.7
通讯作者：
Gabius, HJ
中科院分区：
文献类型：
--
作者：
André, S;Frisch, B;Gabius, HJ
目的。细胞糖偶联物中常见的寡糖是多种内源性凝集素的配体。C型凝集素和半乳糖凝集素对β-半乳糖苷的重叠特异性可以降低碳水化合物配体依赖的药物靶向的靶向性。本研究的目的是探索簇状糖苷设计的配基呈现和结构的不同特征，以区分去唾液酸糖蛋白特异性(C型)凝集素和半乳糖凝集素。在没有和存在竞争性抑制剂的情况下，评估标记的糖受体与两种基质固定(NEO)糖蛋白和细胞的结合程度。该组合由合成的单价、双价和三价糖苷组成，具有两个间隔基长度，半乳糖或乳糖作为配体部分。与肝细胞和巨噬细胞的C型凝集素相比，二价和三价糖苷对Galectins-1和-3不产生显著的糖苷簇效应。此外，这些不依赖钙离子的半乳糖苷结合蛋白更倾向于以乳糖糖苷为配体，而间隔区长度要求相当相似。以半乳糖/半乳糖为配体的三价簇糖苷明显区别于C型凝集素和半乳糖凝集素。因此，对C型凝集素药物输送的Galectins的不良副反应将是最小的。
Purpose. Common oligosaccharides of cellular glycoconjugates are ligands for more than one type of endogenous lectin. Overlapping specificities to beta-galactosides of C-type lectins and galectins can reduce target selectivity of carbohydrate-ligand-dependent drug targeting. The purpose of this study is to explore distinct features of ligand presentation and structure for design of cluster glycosides to distinguish between asialoglycoprotein-specific (C-type) lectins and galectins.Methods. Extent of binding of labeled sugar receptors to two types of matrix-immobilized (neo)glycoproteins and to cells was evaluated in the absence and presence of competitive inhibitors. This panel comprised synthetic mono-, bi-, and trivalent glycosides with two spacer lengths and galactose or lactose as ligand part.Results. In contrast to C-type lectins of hepatocytes and macrophages, bi- and trivalent glycosides do not yield a notable glycoside cluster effect for galectins-1 and -3. Also, these Ca2+-independent galactoside binding proteins prefer to home in on lactose-bearing glycosides relative to galactose as ligand, while spacer length requirements were rather similar.Conclusions. Trivalent cluster glycosides with Gal/GalNAc as ligand markedly distinguish between C-type lectins and galectins. Undesired side reactivities to galectins for C-type lectin drug delivery will thus be minimal.