Carbamate-Linked Lactose: Design of Clusters and Evidence for Selectivity to Block Binding of Human Lectins to (Neo)Glycoproteins with Increasing Degree of Branching and to Tumor Cells
Carbamate-Linked Lactose: Design of Clusters and Evidence for Selectivity to Block Binding of Human Lectins to (Neo)Glycoproteins with Increasing Degree of Branching and to Tumor Cells
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DOI：
10.1021/bc900152w
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发表时间：
2009-09-01
影响因子：
4.7
通讯作者：
Wittmann, Valentin
中科院分区：
文献类型：
--
作者：
Andre, Sabine;Specker, Daniel;Wittmann, Valentin
各种致病过程由蛋白质（凝集素）-聚糖相互作用驱动。尤其涉及细胞聚糖分支末端的β-半乳糖苷。这些新的见解激发了设计有效抑制剂来阻断凝集素的兴趣。作为实现这一目标的一步，我们制备了一系列的十个一至四价糖化合物与乳糖作为一个共同的头基。为了获得用于随后形成氨基甲酸酯的活性碳酸酯，确定了从端基异构体未保护的乳糖容易合成纯异构体的条件。为了探测经常遇到的人类凝集素家族内的多样性，我们选择了代表性的成员从三个亚组的粘附/生长调节半乳糖凝集素受体。在固相分析中，通过使用具有不同程度的聚糖分支的四种（新）糖蛋白作为基质来解释聚糖展示的多样性。与游离乳糖相比，乳糖簇的抑制效力增加的情况被揭示。相对抑制的程度并不直接与糖化合物的化合价，并依赖于凝集素的类型。值得注意的是，对于筛选方案，阻断的功效似乎随着基质糖蛋白中聚糖分支程度的增加而降低。与肿瘤细胞的结合受到半乳糖凝集素-3和-4的选择性损害。代表性化合物不损害癌细胞尖端的生长，每次测定的乳糖部分浓度为5 mM（价校正值）。报道的生物活性和描绘其调制凝集素和聚糖的结构参数设置为进一步设计的选择性抑制剂和测定程序的指导性的例子。
Various pathogenic processes are driven by protein(lectin)-glycan interactions. especially involving beta-galactosides at branch ends of cellular glycans. These emerging insights fuel the interest to design potent inhibitors to block lectins. As a step toward this aim, we prepared a series of ten mono- to tetravalent glycocompounds with lactose as a common headgroup. To obtain activated carbonate for ensuing carbamate formation, conditions for the facile synthesis of pure isomers from anomerically unprotected lactose were identified. To probe for the often encountered intrafamily diversity of human lectins, we selected representative members from the three subgroups of adhesion/growth-regulatory galectins as receptors. Diversity of the glycan display was accounted for by using four (neo)glycoproteins with different degrees of glycan branching as matrices in solid-phase assays. Cases of increased inhibitory potency of lactose clusters compared to free lactose were revealed. Extent of relative inhibition was not directly associated with valency in the glycocompound and depended on the lectin type. Of note for screening protocols, efficacy of blocking appeared to decrease with increased degree of glycan branching in matrix glycoproteins. Binding to tumor cells was impaired with selectivity for galectins-3 and -4. Representative compounds did not impair growth of carcinoma cells tip to a concentration of 5 mM of lactose moicties (valence-corrected value) per assay. The reported bioactivity and the delineation of its modulation by structural parameters of lectins and glycans set instructive examples for the further design of selective inhibitors and assay procedures.