Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule
Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule
复制标题
DOI：
10.1126/science.295.5557.1086
复制
发表时间：
2002-02-08
期刊：
影响因子：
56.9
通讯作者：
Bodary, SC
中科院分区：
文献类型：
--
作者：
Gadek, TR;Burdick, DJ;Bodary, SC
白细胞功能抗原-1 （LFA-1）和细胞间粘附分子-1 （ICAM-1）之间的蛋白-蛋白相互作用对淋巴细胞和免疫系统功能至关重要。在这里，我们报道了ICAM-1的连续非线性表位转移到一个小分子框架中，负责与LFA-1的关联。这些LFA-1拮抗剂结合LFA-1，阻断ICAM-1的结合，抑制混合淋巴细胞反应（MLR），其效价显著高于环孢素a。此外，与LFA-1抗体相比，它们在体内表现出显著的抗炎作用。这些结果证明了非线性蛋白表位的小分子模拟物和蛋白表位本身在鉴定新药方面的作用。
The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.