André S, Frisch B, Kaltner H, Desouza D L, Schuber F, Gabius H J
Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, Germany.
Pharm Res. 2000 Aug;17(8):985-90. doi: 10.1023/a:1007535506705.
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.
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.
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.
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.
细胞糖缀合物的常见寡糖是不止一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会降低碳水化合物配体依赖性药物靶向的目标选择性。本研究的目的是探索配体呈现和结构的独特特征，以设计簇糖苷来区分去唾液酸糖蛋白特异性（C型）凝集素和半乳糖凝集素。
在存在和不存在竞争性抑制剂的情况下，评估标记的糖受体与两种类型的基质固定化（新）糖蛋白以及细胞的结合程度。该组包括具有两种间隔长度且以半乳糖或乳糖作为配体部分的合成单价、二价和三价糖苷。
与肝细胞和巨噬细胞的C型凝集素不同，二价和三价糖苷对半乳糖凝集素-1和-3不会产生显著的糖苷簇效应。此外，这些不依赖Ca2+的半乳糖苷结合蛋白相对于作为配体的半乳糖，更倾向于靶向含乳糖的糖苷，而对间隔长度的要求相当相似。
以Gal/GalNAc作为配体的三价簇糖苷能显著区分C型凝集素和半乳糖凝集素。因此，对于C型凝集素药物递送，对半乳糖凝集素的不必要的副反应将降至最低。
