Persubstituted cyclodextrin-based glycoclusters as inhibitors of protein-carbohydrate recognition using purified plant and mammalian lectins and wild-type and lectin-gene-transfected tumor cells as targets
Persubstituted cyclodextrin-based glycoclusters as inhibitors of protein-carbohydrate recognition using purified plant and mammalian lectins and wild-type and lectin-gene-transfected tumor cells as targets
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DOI：
10.1021/bc0340666
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发表时间：
2004-01-01
影响因子：
4.7
通讯作者：
Gabius, HJ
中科院分区：
文献类型：
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作者：
André, S;Kaltner, H;Gabius, HJ
多价糖簇由于其对临床相关糖受体的靶特异性而具有成为药物的潜力。它们的应用还可以提供关于两个空间因素对结合的影响的基本见解，即，凝集素中配体的拓扑结构（分支模式，簇呈现）和碳水化合物识别结构域。以6-脱氧-6-碘-β-环糊精为原料，经无保护的3-（3-硫代乙酰丙酰胺基）丙基糖苷（半乳糖、乳糖和N-乙酰乳糖胺）的硫醇钠亲核取代，合成了全取代大环化合物。所产生的糖簇首先在固相测定中作为竞争性抑制剂进行测试。槲寄生的植物毒素和人血清中的免疫球蛋白G组分明显敏感。检测到七价形式的每个半乳糖部分相对于游离乳糖的抑制效力增加近400倍（相对于游离半乳糖增加217倍）。因此，这些糖簇可以有效地干扰例如异种抗原依赖性超急性排斥。在测试的半乳糖凝集素选自这个家庭的粘附和生长调节内源性凝集素，取代的β-环糊精作为传感器描绘两个二聚体原型蛋白质之间的拓扑差异。与嵌合型半乳糖凝集素-3，肿瘤转移的介质，相对较强的反应性，半乳糖凝集素之间的糖簇结合的选择性。同样重要的是，配体展示的几何形状（大簇、双触角或三触角N-聚糖）对抑制效力有影响。为了进一步确定存在于细胞表面而不是溶液中的不同半乳糖凝集素的敏感性，我们建立了稳定转染的肿瘤细胞克隆。我们检测到对多价抑制剂存在的显著响应。因此，这种类型的化学支架具有良好的药理学特性，可用于半乳糖凝集素和配体类型选择性糖簇的设计。
Multivalent glycoclusters have the potential to become pharmaceuticals by virtue of their target specificity toward clinically relevant sugar receptors. Their application can also provide fundamental insights into the impact of two spatial factors on binding, i.e., topologies of ligand (branching mode, cluster presentation) and carbohydrate recognition domains in lectins. Persubstituted macrocycles derived from nucleophilic substitution of iodide from heptakis 6-deoxy-6-iodo-beta-cyclodextrin by the unprotected sodium thiolate of 3-(3-thioacetyl propionamido)propyl glycosides (galactose, lactose and N-acetyllactosamine) were prepared. The produced glycoclusters were first tested as competitive inhibitors in solid-phase assays. A plant toxin from mistletoe and an immunoglobulin G fraction from human serum were markedly susceptible. A nearly 400-fold increase in inhibitory potency of each galactose moiety in the heptavalent form relative to free lactose (217-fold relative to free galactose) was detected. Thus, these glycoclusters can efficiently interfere, for example, with xenoantigen-dependent hyperacute rejection. Among the tested galectins selected from this family of adhesion- and growth-regulatory endogenous lectins, the substituted beta-cyclodextrins acted as sensors to delineate topological differences between the two dimeric prototype proteins. The relatively strong reactivity with chimera-type galectin-3, a mediator of tumor metastasis, disclosed selectivity for glycocluster binding among galectins. Equally important, the geometry of ligand display (maxiclusters, bi- or triantennary N-glycans) made its mark on the inhibitory potency. To further determine the sensitivity of a distinct galectin presented on the cell surface and not in solution, we established a stably transfected tumor cell clone. We detected a significant response to presence of the multivalent inhibitor. This type of chemical scaffold with favorable pharmacologic properties might thus be exploited for the design of galectin- and ligand-type-selective glycoclusters.