Bifunctional ligands that target cells displaying the αvβ3 integrin
Bifunctional ligands that target cells displaying the αvβ3 integrin
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DOI：
10.1002/cbic.200600339
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发表时间：
2007-01-02
期刊：
影响因子：
3.2
通讯作者：
Kiessling, Laura L.
中科院分区：
文献类型：
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作者：
Owen, Robert M.;Carlson, Coby B.;Kiessling, Laura L.
长期以来人们一直在寻求消除肿瘤细胞的策略。我们设想一种小分子可以用来用免疫原性碳水化合物修饰有问题的细胞并引发免疫反应。为此，我们描述了具有两个功能基序的双功能配体的合成：一个结合细胞表面蛋白，另一个结合天然存在的人类抗体。我们的缀合物将基于 RGD 的肽模拟物与碳水化合物抗原半乳糖基-α(1-3)半乳糖 [Gal α(1-3)Gal 或 α-Gal] 结合到展示 α(v)beta(3) 整联蛋白的靶细胞。为了生成这种双功能配体，我们设计并合成了RGD模拟物1b和2c，它们具有用于修饰的游离氨基。这些化合物被用来生成双功能衍生物1c和2d，其中方酸二甲酯是关键；因此，我们的合成方法是模块化的。为了评估我们的肽模拟物与目标α(v)β(3)展示细胞的结合，我们实施了细胞粘附测定。该测定的结果表明，设计的小分子配体抑制α(v)β(3)依赖性细胞粘附。此外，我们最有效的双功能配体对 α(v)β(3) 比相关的 α(v)β(5) 整联蛋白表现出高度选择性（4000 倍），这一结果预示着其在特定细胞靶向中的实用性。最后，我们证明双功能配体可以结合α(v)β(3)阳性细胞并招募人抗Gal抗体。这些结果表明整联蛋白结合部分和抗Gal结合部分可以同时起作用。这种类型的双功能缀合物有助于开发利用内源抗体靶向癌细胞的新方法。我们预计我们的可修饰α(v)β(3)结合配体将在多种应用中具有价值，包括药物输送和肿瘤靶向。
Strategies to eliminate tumor cells have long been sought. We envisioned that a small molecule could be used to decorate the offending cells with immunogenic carbohydrates and evoke an immune response. To this end, we describe the synthesis of bifunctional ligands possessing two functional motifs: one binds a cell-surface protein and the other binds a naturally occurring human antibody. Our conjugates combine an RGD-based peptidomimetic, to target cells displaying the alpha(v)beta(3) integrin, with the carbohydrate antigen galactosyl-alpha(1-3)galactose [Gal alpha(1-3)Gal or alpha-Gal]. To generate such bifunctional ligands, we designed and synthesized RGD mimetics 1 b and 2 c, which possess a free amino group for modification. These compounds were used to generate bifunctional derivatives 1 c and 2 d, with dimethyl squarate serving as the linchpin; thus, our synthetic approach is modular. To evaluate the binding of our peptidomimetics to the target alpha(v)beta(3)-displaying cells, we implemented a cell-adhesion assay. Results from this assay indicate that the designed small-molecule ligands inhibit alpha(v)beta(3)-dependent cell adhesion. Additionally, our most effective bifunctional ligand exhibits a high degree of selectivity (4000-fold) for alpha(v)beta(3) over the related alpha(v)beta(5) integrin, a result that augurs its utility in specific cell targeting. Finally, we demonstrate that the bifunctional ligands can bind to alpha(v)beta(3)-positive cells and recruit human anti-Gal antibodies. These results indicate that both the integrin-binding and the anti-Gal-binding moieties can act simultaneously. Bifunctional conjugates of this type con facilitate the development of new methods for targeting cancer cells by exploiting endogenous antibodies. We anticipate that our modifiable alpha(v)beta(3)-binding ligands will be valuable in a variety of applications, including drug delivery and tumor targeting.