An array-based method to identify multivalent inhibitors.
An array-based method to identify multivalent inhibitors.
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DOI：
10.1021/ja100608w
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发表时间：
2010-07-21
影响因子：
15
通讯作者：
Gildersleeve JC
中科院分区：
文献类型：
--
作者：
Zhang Y;Li Q;Rodriguez LG;Gildersleeve JC
碳水化合物-蛋白质相互作用在多种生物过程中起关键作用，并且这些相互作用的激动剂/拮抗剂可用作生物探针和治疗剂。大多数碳水化合物结合蛋白通过形成多价复合物实现紧密结合。因此，配体结构和呈递都有助于识别。由于有许多潜在的结构，间距和方向的组合考虑和最佳的一个不能预测，高通量的方法来分析碳水化合物-蛋白质相互作用和设计抑制剂是有吸引力的。在这份报告中，我们开发了一种策略来改变聚糖阵列表面上的新糖蛋白密度。将这种呈现特征与聚糖结构和聚糖密度的变化相结合，以产生具有约600种聚糖结构和呈现组合的阵列。独特的阵列平台允许区分阵列表面上不同类型的多价复合物。为了说明这种形式的优点，它被用来快速识别各种凝集素的多价探针。首先用几种植物凝集素测试了新阵列，包括刀豆球蛋白A（conA）、毛野豌豆异凝集素B4（VVL-B4）和蓖麻凝集素（RCA 120）。接下来，它被用于快速鉴定铜绿假单胞菌凝集素I（PA-IL）（一种参与铜绿假单胞菌机会性感染的关键蛋白）和小鼠巨噬细胞半乳糖型凝集素（mMGL-2）（一种在抗原呈递细胞上表达的蛋白，其可用作疫苗靶向受体）的有效多价抑制剂。该方法的优点是不需要关于凝集素/受体的结构信息来获得多价抑制剂/探针。
Carbohydrate-protein interactions play a critical role in a variety of biological processes, and agonists/antagonists of these interactions are useful as biological probes and therapeutic agents. Most carbohydrate-binding proteins achieve tight binding through formation of a multivalent complex. Therefore, both ligand structure and presentation contribute to recognition. Since there are many potential combinations of structure, spacing, and orientation to consider and the optimal one cannot be predicted, high-throughput approaches for analyzing carbohydrate-protein interactions and designing inhibitors are appealing. In this report, we develop a strategy to vary neoglycoprotein density on a surface of a glycan array. This feature of presentation was combined with variations in glycan structure and glycan density to produce an array with approximately 600 combinations of glycan structure and presentation. The unique array platform allows one to distinguish between different types of multivalent complexes on the array surface. To illustrate the advantages of this format, it was used to rapidly identify multivalent probes for various lectins. The new array was first tested with several plant lectins, including concanavalin A (conA), Vicia villosa isolectin B4 (VVL-B4), and Ricinus communis agglutinin (RCA120). Next, it was used to rapidly identify potent multivalent inhibitors of Pseudomonas aeruginosa lectin I (PA-IL), a key protein involved in opportunistic infections of P. aeruginosa, and mouse macrophage galactose-type lectin (mMGL-2), a protein expressed on antigen presenting cells that may be useful as a vaccine targeting receptor. An advantage of the approach is that structural information about the lectin/receptor is not required to obtain a multivalent inhibitor/probe.
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影响因子：
15
作者：
Gordus, Andrew;MacBeath, Gavin
通讯作者：
MacBeath, Gavin
影响因子：
15
作者：
Gestwicki, JE;Cairo, CW;Kiessling, LL
通讯作者：
Kiessling, LL
DOI：
10.1016/j.bbrc.2008.04.120
发表时间：
2008-07-11
影响因子：
3.1
作者：
Kato, Kentaro;Takeuchi, Hideyuki;Irimura, Tatsuro
通讯作者：
Irimura, Tatsuro
影响因子：
4.7
作者：
Gildersleeve, Jeffrey C.;Oyelaran, Oyindasola;Allred, Benjamin
通讯作者：
Allred, Benjamin
影响因子：
3.5
作者：
Cioci, G;Mitchell, EP;Imberty, A
通讯作者：
Imberty, A