Synthesis of small molecules for inhition of chlamydial growth

我们已经开发出具有强大的抗衣原体活性的神经酰胺衍生物。不同衣原体菌株与已知抗衣原体化合物之间的效力、结构、体外测试和初步比较研究表明，这些分子具有一种尚未描述的新的作用机制。然而，我们基于大约30种不同化合物的初步SAR表明，最有可能的靶向是鞘脂特异的生物分子，这些生物分子可能是衣原体鞘脂获取机制的重要组成部分。我们的目标是进一步开发分子集合，并测试它们对衣原体生命周期的影响。将应用化学合成和各种生物测试来确定有效的效应物。我们将合成这些效应器的变体，使我们能够交联、下拉和识别潜在的分子靶标分子。设想了允许解剖分子转化和受感染细胞内单个脂类的运输的探针。另一个重要目标是确定潜在的药物靶点，并建立允许快速开发新的抗衣原体化合物的体外检测方法。如果宿主生物分子是这些化合物的靶标，那么这些靶标也很可能是关于其他细胞内病原体的有趣的研究。该提案一方面涉及化学合成和生物有机分析的发展，另一方面涉及细胞生物学和感染生物学。

We have developed ceramide derivatives with potent anti-chlamydial activity. Potency, structure, in vitro assays and preliminary comparative studies between different chlamydial strains with known anti-chlamydial compounds suggest that these molecules have a novel not yet described mechanism of action. Our preliminary SAR, based on about 30 different compounds however indicates that most likely sphingolipid-specific biomolecules are targeted that could be important components of the chlamydial sphingolipid-acquisition machinery. Our objective is to further develop collections of molecules and to test their effect on the chlamydial life cycle. Chemical synthesis and various bioassays will be applied to identify potent effectors. We will synthesize variants of these effectors that will enable us to crosslink, pull down and identify potential molecular target molecules. Probes are envisioned allowing for dissecting molecular conversion and trafficking of individual lipids within infected cells. An additional important goal is to identify potential pharmaceutical targets and to establish in vitro assays that allow for rapid development of novel antichlamydial compounds. If host biomolecules are targeted by the compounds, it is well possible that these targets could also be interesting to be investigated with regard to other intracellular pathogens. The proposal covers chemical synthesis and bioorganic assay development on the one hand and cell- and infection biology on the other hand.