Target Identification

超过60%的药物靶标是膜蛋白。然而，目前只有一种抗结核药物 药物乙胺丁醇靶向M.结核病表明，这种巨大的潜力在很大程度上是 未使用M。结核最近发现了一种新的靶向ATP的二芳基喹啉药物 合酶的M.结核病和超过活动的两个主要结核病药物异烟肼和利福平 证明了这个假设是正确的。因此，我们选择了11个 约800个推定的M.结核分枝杆菌生长所必需的蛋白质。 在体外或在小鼠中的结核病。选择这些蛋白质以涵盖广泛的功能，例如 必需营养物质的运输、细胞分裂、蛋白质和细胞壁的输出以及脂质的生物合成。 此外，它们足够小，可以适用于当前的固态NMR方法。外 膜蛋白作为药物靶点提供了巨大的优势，抑制剂可能不需要穿过 外膜是分枝杆菌中非常有效的渗透屏障。此外他们 很可能代表新的药物靶点，因为它们似乎与其他靶点没有任何相似性。 proteins.因此，我们在我们的初始靶点列表中包括了七种假定的外膜蛋白， 其没有已知的功能。这个项目的目标是验证18个选定的潜力 膜蛋白作为药物靶点，以阐明6种蛋白的生理功能， 同源物，并确定这些蛋白质中的一些推定的相互作用伙伴。

More than 60% of all drug targets are membrane proteins. However, only one of the current antituberculous drugs, ethambutol, targets membrane proteins of M. tuberculosis indicating that this vast potential is largely untapped for M. tuberculosis. The recent discovery of a new diarylquinoline drug that targets the ATP synthase of M. tuberculosis and exceeds the activities of the two main TB drugs isoniazid and rifampin provides proof of principle that this assumption is correct. Therefore, we have selected 11 out of approximately 800 putative inner membrane proteins of M. tuberculosis, which are essential for growth of M. tuberculosis in vitro or in mice. These proteins were selected to cover a broad variety of functions, such as transport of essential nutrients, cell division, export of proteins and cell wall and lipid biosynthesis. Furthermore, they are sufficiently small to be amenable to current solid-state NMR methods. Outer membrane proteins offer the tremendous advantage as drug targets that inhibitors may not need to cross the outer membrane which is an extremely efficient permeability barrier in mycobacteria. In addition, they are likely to represent novel drug targets because they do not appear to show any similarity to other proteins. Therefore, we included seven putative outer membrane proteins in our list of initial targets, six of which have no known function. The goal of this project is to validate the potential of the 18 selected membrane proteins as drug targets, to elucidate the physiological function of the 6 proteins with no known homologs and to identify putative interaction partners for some of these proteins.