Structure-activity relationship of synthetic Toll-like receptor 4 agonists
Structure-activity relationship of synthetic Toll-like receptor 4 agonists
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DOI：
10.1074/jbc.m310760200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Hershberg, RM
中科院分区：
文献类型：
--
作者：
Stöver, AG;Correia, JD;Hershberg, RM
关于脂多糖的脂质A部分的结构变化对通过Toll样受体4复合物激活细胞的影响，仍然存在重要的问题。我们已经研究了一系列的合成脂质A模拟化合物被称为氨基烷基氨基葡萄糖苷磷酸盐，其中的二级酰基链的长度已经系统地变化。使用人单核细胞的转录谱和Toll样受体4复合物细胞转染子的响应，我们证明了Toll样受体4激活的二级酰基链的长度的明确依赖性。具有长度小于8个碳的仲酰基链的化合物具有显著降低的活性，并且左侧仲酰基链的取代对这些分子的Toll样受体4激动剂活性具有最重要的影响。这些化合物的结构-功能关系通过诱导体内给药后的趋化因子和细胞因子进行评估，与基于细胞的研究密切相关。这组新的合成脂质A模拟物将用于基于Toll样受体4的研究，并可能具有作为独立免疫调节剂的临床实用性。
Important questions remain regarding the impact of variations in the structure of the lipid A portion of lipopolysaccharide on activation of cells via the Toll-like receptor 4 complex. We have studied a series of synthetic lipid A mimetic compounds known as aminoalkyl glucosaminide phosphates in which the length of the secondary acyl chain has been systematically varied. Using transcriptional profiling of human monocytes and responses of Toll-like receptor 4 complex cell transfectants, we demonstrate a clear dependence of length on secondary acyl chain on Toll-like receptor 4 activation. Compounds with secondary acyl chains less than eight carbons in length have dramatically reduced activity, and substitutions of the left-sided secondary acyl chain had the most important effect on the Toll-like receptor 4 agonist activity of these molecules. The structure-function relationships of these compounds assessed via the induction of chemokines and cytokines following in vivo administration closely mirrored those seen with cell-based studies. This novel set of synthetic lipid A mimetics will be useful for Toll-like receptor 4-based investigations and may have clinical utility as stand-alone immunomodulators.