Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach
Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach
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DOI：
10.1002/cbic.200500171
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发表时间：
2005-10-01
期刊：
影响因子：
3.2
通讯作者：
Waldmann, H
中科院分区：
文献类型：
--
作者：
Manger, M;Scheck, M;Waldmann, H
蛋白质磷酸化和去磷酸化反应是无数生物过程的核心。异常的蛋白质磷酸化有助于许多人类疾病的发展，包括癌症和糖尿病。[1]由于这种生物学上的重要性，催化蛋白磷酸化的蛋白激酶及其拮抗剂蛋白磷酸酶（PPs）已经成为迅速增长的药物化学和化学生物学研究计划的焦点。[2-5]几种细菌病原体产生与毒力有关的真核样蛋白磷酸酶。一个特别重要的例子是结核分枝杆菌，它是结核病（TB）的病原体，也是世界各地死亡的主要原因。[6]M.结核病有两种功能性磷酸酶，MptpA和MptpB。[7]这些酶由生长中的分枝杆菌细胞分泌。据信它们通过使参与干扰素-g信号通路的蛋白质去磷酸化来介导宿主细胞中分枝杆菌的生存。[8，9]世界上大约三分之一的人口感染了M.结核病，并且耐药分枝杆菌的传播越来越多。因此，越来越需要开发用于治疗结核病的新治疗剂。鉴于这种迫切的需求，Mptps已被提议作为新的潜在抗结核药物靶标。[9]然而，迄今为止，这些酶的抑制剂尚未被描述。在这里，我们描述了MptpA抑制剂的发现，通过两种不同的和互补的方法，用于识别在筛选集合中的初始命中，即天然产物spilled和基于片段的库开发。我们以前提出的概念，生物活性的天然产物应被视为进化选择和生物学prevalidated抑制剂开发的起点。[10]基于这一原理和MptpA是酪氨酸磷酸酶的事实，[7，11]我们研究了已经用作发现新类型磷酸酶抑制剂的指导结构的天然产物及其类似物[12，13]是否可以用于鉴定第一种Mptp抑制剂。最初认为stevastelin（方案1）是开发MptpA抑制剂的可能起点。
Protein phosphorylation and dephosphorylation reactions are at the heart of innumerable biological processes. Aberrant protein phosphorylation contributes to the development of many human diseases including cancer and diabetes.[1] Due to this biological importance, protein kinases, which catalyse protein phosphorylation, and their antagonists, protein phosphatases (PPs), have moved into the focus of a rapidly growing number of medicinal-chemistry and chemicalbiology research programs.[2–5] Several bacterial pathogens produce eukaryotic-like protein phosphatases that have been implicated in virulence. A particularly important case is Myobacterium tuberculosis, which is the causative agent of tuberculosis (TB) and a major cause of mortality around the world.[6] M. tuberculosis has two functional phosphatases, MptpA and MptpB.[7] These enzymes are secreted by growing mycobacterial cells. They are believed to mediate mycobacterial survival in host cells by dephosphorylating proteins that are involved in interferon-g signaling pathways.[8, 9] About one third of the world’s population is infected with M. tuberculosis, and there is an increasing spread of drug-resistant mycobacteria. Therefore, there is a growing need for the development of new therapeutic agents for the treatment of tuberculosis. In the light of this urgent demand, the Mptps have been proposed as new potential anti-TB drug targets.[9] However, to date, inhibitors of these enzymes have not been described. Here we describe the discovery of MptpA inhibitors by two different and complementary approaches for the identification of initial hits in screening collections, namely natural-productinspired and fragment-based library development. We have previously forwarded the notion that biologically active natural products should be regarded as evolutionarily selected and biologically prevalidated starting points for inhibitor development.[10] Based on this principle and the fact that MptpA is a tyrosine phosphatase,[7, 11] we have investigated whether natural products and their analogues that have already served as guiding structures for the discovery of new classes of phosphatase inhibitors [12, 13] could be employed for the identification of the first Mptp inhibitors. Initially the stevastelins (Scheme 1) were considered as possible starting points for the development of MptpA inhibitors.