Non-carbo hydrate inhibitors of the lectin DC-SIGN
Non-carbo hydrate inhibitors of the lectin DC-SIGN
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DOI：
10.1021/ja072944v
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发表时间：
2007-10-24
影响因子：
15
通讯作者：
Kiessling, Laura L.
中科院分区：
文献类型：
--
作者：
Borrok, M. Jack;Kiessling, Laura L.
树突状细胞表面存在C型凝集素、树突状细胞特异性的细胞间黏附分子3-抓取非整合素(DC-SIGN)。它可以介导树突状细胞和T淋巴细胞之间的黏附，并促进抗原的捕获和提呈。许多病原体可以利用DC-SIGN结合达到邪恶的目的。例如，DC-SIGN可以促进像HIV-1这样的病毒的传播。或者，一些微生物(例如结核分枝杆菌)利用它们与DC-SIGN相互作用的能力来逃避免疫检测。DC-SIGN的不同作用为寻找可用于探索其不同功能的配体提供了动力。这类化合物还可以作为治疗线索。以前研究的DC-SIGN配体大多是甘露糖或岩藻糖衍生的单糖或低聚糖，其抑制常数在0.1-10 mM之间。为了确定具有更强的DC-SIGN阻断特性的单价配体，我们设计了一种高通量的基于荧光的竞争分析方法。本试验提供了有效的非碳水化率小分子抑制剂(IC_(50)值1.6-10微米)。这些化合物不仅阻断DC-SIGN-碳水化合物的相互作用，而且还阻断DC-SIGN介导的细胞黏附。因此，我们期望这些非碳水化合物能被用来阐明DC-SIGN在发病机制和免疫功能中的作用。
The C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is found on the surface of dendritic cells. It can mediate adhesion between dendritic cells and T lymphocytes and facilitate antigen capture and presentation. Many pathogens can exploit DC-SIGN binding for nefarious purposes. For example, DC-SIGN can facilitate the dissemination of viruses, like HIV-1. Alternatively, some microbes (e.g., Mycobacterium tuberculosis) use their ability to interact with DC-SIGN to evade immune detection. The diverse roles attributed to DC-SIGN provide impetus to identify ligands that can be used to explore its different functions. Such compounds also could serve as therapeutic leads. Most of the DC-SIGN ligands studied previously are mannose- or fucose-derived monosaccharides or oligosaccharides with inhibitory constants in the range of 0.1 -10 mM. To identify monovialent ligands with more powerful DC-SIGN blocking properties, we devised a high-throughput fluorescence-based competition assay. This assay afforded potent non-carbohyd rate, small molecule inhibitors (IC50 values of 1.6-10 mu M). These compounds block not only DC-SIGN-carbohydrate interactions but also DC-SIGN-mediated cell adhesion. Thus, we anticipate that these non-carbohyd rate inhibitors can be used to illuminate the role of DC-SIGN in pathogenesis and immune function.