Identification of glycolytic pathway inhibitors against Trypanosoma cruzi pyruvat

克氏锥虫糖酵解途径抑制剂的鉴定

基本信息

  • 批准号:
    8207347
  • 负责人:
  • 金额:
    $ 2.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-22 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to discover and optimize selective inhibitors of pyruvate kinase (PYK) from two protist parasites: Trypanosoma cruzi causes Chagas' disease throughout the Americas, including Texas and other southern regions of the United States, whereas two subspecies of Trypanosoma brucei cause sleeping sickness in areas of sub-Saharan Africa. Collectively parasites of the trypanosomatid family infect 30 million people worldwide (~500 million live in endemic areas), and account for ~130K deaths annually. Given their debilitating and prevalent nature, they impose a heavy medical, economic and social burden on entire populations primarily in the developing world. The problem is further exacerbated by the fact that existing treatments have progressed little in the past 50 years, and current drugs show high toxicity and poor efficacy. Glycolysis is essential in the infective stages of T. cruzi and T. brucei, and is therefore a promising drug target. Inhibitors of glycolytic enzymes such as PYK may thus serve as lead compounds for the development of new drugs. Furthermore, TbPYK has been validated as a drug target by RNAi, and detailed structural information is also available. In addition, trypanosomatid PYKs show significant differences from their human counterparts, especially with regard to allosteric properties. The proposed research has as specific aims: (1) To develop and validate qHTS assays mounted on the NCGC high-throughput screening platform for T. cruzi and T. brucei PYKs. (2) To explore a novel approach to HTS with assays containing the activator F16BP, thereby ensuring that the target enzyme will be in its activated conformation. The effector-bound (or R-state) conformation not only corresponds to the predominant conformation in vivo (for example, fructose bisphosphate levels are normally saturating in T. brucei cells), but is also a more rigid structure, with the consequence that inhibitors binding to R-state binding sites are likely to be entropically favoured. (3) To use these assays to screen the Molecular Library Small Molecule Repository (MLSMR) containing more than 300,000 small molecules. Unique structural features of trypanosomatid PYK (compared with the corresponding human enzymes) will be exploited for the discovery of selective inhibitors of these enzymes. (4) To confirm the potency of these compounds in a panel of secondary hit validation assays and to test their specificity in kinetic and selectivity assays, and to further improve the potency of the most promising molecules thus obtained by structure-based methods, analogue synthesis and medicinal chemical principles. (5) To determine the mode of action of the most promising molecules by enzyme assays, protein crystallography and biophysical measurements. (6) To test compounds displaying the highest potency for their ability to inhibit growth of cultured trypanosomatid cells representing pathogenic stages of the parasites, as well as for lack of toxicity toward cultured human cells. PUBLIC HEALTH RELEVANCE: Sleeping sickness in sub-Saharan Africa and Chagas' disease in the Americas (including the southern United States) cause severe public health and economic burdens on populations that are often already caught in a tragic cycle of poverty, poor nutrition and disease. Millions of people worldwide are infected by these potentially fatal diseases and hundreds of millions are at risk. Existing treatments have developed little in the past 50 years, and suffer from toxicity, inefficiency and resistance; the goal of this project is to develop lead drugs that will be suitable for entry into pre-clinical trials.
描述(由申请人提供):本项目的目标是发现和优化两种原生生物寄生虫的丙酮酸激酶(PYK)的选择性抑制剂:克氏锥虫在整个美洲引起查加斯病,包括德克萨斯州和美国其他南部地区,而布氏锥虫的两个亚种在撒哈拉以南非洲地区引起昏睡病。锥虫科的寄生虫在全世界感染了3000万人(约5亿人生活在流行地区),每年造成约13万人死亡。鉴于其致人衰弱和普遍存在的性质,它们给全体人民,主要是发展中世界的全体人民带来沉重的医疗、经济和社会负担。在过去的50年里,现有的治疗方法进展甚微,目前的药物显示出高毒性和低疗效,这一事实进一步加剧了这一问题。糖酵解在T. cruzi和T.布鲁氏菌,因此是一个有前途的药物靶点。因此,糖酵解酶抑制剂如PYK可作为开发新药的先导化合物。此外,TbPYK已通过RNAi被验证为药物靶标,并且也可获得详细的结构信息。此外,锥虫PYK显示出与其人类对应物的显著差异,特别是在变构特性方面。本研究的具体目标是:(1)建立并验证NCGC高通量筛选平台上的qHTS检测方法。cruzi和T.布鲁氏菌PYKs. (2)探索一种新的方法,HTS与含有激活剂F16 BP的测定,从而确保目标酶将在其激活的构象。效应子结合(或R状态)构象不仅对应于体内的主要构象(例如,果糖二磷酸水平在T.布氏细胞),但也是更刚性的结构,结果是结合到R-状态结合位点的抑制剂可能是熵有利的。(3)使用这些检测来筛选包含超过300,000个小分子的分子库小分子库(MLSMR)。锥虫PYK的独特结构特征(与相应的人类酶相比)将被用于发现这些酶的选择性抑制剂。(4)在一组二次命中验证试验中确认这些化合物的效价,并在动力学和选择性试验中检测其特异性,并进一步提高通过基于结构的方法、类似物合成和药物化学原理获得的最有前途的分子的效价。(5)通过酶分析、蛋白质晶体学和生物物理测量确定最有希望的分子的作用模式。(6)为了测试化合物显示出抑制代表寄生虫致病阶段的培养锥虫细胞生长的能力以及对培养的人细胞无毒性的最高效力。 公共卫生相关性:撒哈拉以南非洲的昏睡病和美洲(包括美国南部)的恰加斯病给往往已经陷入贫穷、营养不良和疾病悲惨循环的人口造成严重的公共卫生和经济负担。全世界有数百万人感染了这些可能致命的疾病,数亿人处于危险之中。现有的治疗方法在过去的50年里几乎没有发展,并且存在毒性,效率低下和耐药性;该项目的目标是开发适合进入临床前试验的先导药物。

项目成果

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Malcolm Douglas Walkinshaw其他文献

Malcolm Douglas Walkinshaw的其他文献

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{{ truncateString('Malcolm Douglas Walkinshaw', 18)}}的其他基金

Inhibitors Against Trypanosomatid Pyruvate Kinases
锥虫丙酮酸激酶抑制剂
  • 批准号:
    8304823
  • 财政年份:
    2011
  • 资助金额:
    $ 2.7万
  • 项目类别:
Inhibitors of Trypanosomatid Phosphoglycerate Mutase and Phosphoglycerate Kinase
锥虫磷酸甘油酸变位酶和磷酸甘油酸激酶抑制剂
  • 批准号:
    8205435
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
Identification of selective inhibitors of phosphofructokinase as lead compounds a
作为先导化合物的磷酸果糖激酶选择性抑制剂的鉴定
  • 批准号:
    8009581
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
Identification of selective inhibitors of phosphofructokinase as lead compounds a
作为先导化合物的磷酸果糖激酶选择性抑制剂的鉴定
  • 批准号:
    8104221
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
Selective inhibitors of phosphoglycerate mutase and phosphoglycerate kinase as le
磷酸甘油酸变位酶和磷酸甘油酸激酶的选择性抑制剂如
  • 批准号:
    8069449
  • 财政年份:
    2010
  • 资助金额:
    $ 2.7万
  • 项目类别:
Discovery of Lead Compounds Against Trypanosomiasis and Leishmaniasis Through Ind
通过 Ind 发现抗锥虫病和利什曼病的先导化合物
  • 批准号:
    7627415
  • 财政年份:
    2009
  • 资助金额:
    $ 2.7万
  • 项目类别:

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