Target Identification

超过60%的药物靶点是膜蛋白。然而，目前只有一种抗结核药物 药物乙胺丁醇针对结核分枝杆菌的膜蛋白，表明这种巨大的潜力在很大程度上是 未发现结核分枝杆菌。新近发现的一种针对三磷酸腺苷的二芳基喹啉类药物 结核分枝杆菌合酶活性超过两种主要抗结核药物异烟肼和利福平 提供了这一假设正确的原则证据。因此，我们从以下项目中选择了11个 大约800种推定的结核分枝杆菌内膜蛋白，它们是结核分枝杆菌生长所必需的。 在体外或在小鼠体内的结核病。这些蛋白质被选择来涵盖广泛的功能，例如 基本营养物质的运输、细胞分裂、蛋白质和细胞壁的输出以及脂肪的生物合成。 此外，它们足够小，可以适用于当前的固态核磁共振方法。外型 膜蛋白提供了作为药物靶点的巨大优势，抑制剂可能不需要跨越这些靶点。 外膜是分枝杆菌极其有效的通透性屏障。此外，他们还 很可能代表新的药物靶点，因为它们似乎与其他 蛋白质。因此，我们在最初的靶点列表中包括了7个假定的外膜蛋白，其中6个 它们没有已知的功能。这个项目的目标是验证18个入选的 以膜蛋白为药物靶点，阐明这6种未知蛋白质的生理功能 并确定其中一些蛋白质可能的相互作用伙伴。

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.