NADH-FUMARATE REDUCTASE--A TARGET AGAINST CHAGAS DISEASE

NADH-富马酸还原酶——对抗南美锥虫病的靶标

基本信息

  • 批准号:
    2076729
  • 负责人:
  • 金额:
    $ 10.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-06-01 至 1999-05-31
  • 项目状态:
    已结题

项目摘要

Trypanosoma cruzi is the causal agent of Chagas' disease, a long lasting, incapacitating and often lethal disease. Approximately 18 million people in Central and South America are infected with this parasite. Although the autochthonous infection in the US is very rare, several cases have been reported occurring as a consequence of blood transfusion or organ transplantation. More over, recent studies have pointed out that 2% (Los Angeles) to 5% (Washington, DC) of the hispanics living in the US are infected. Not only these people may contribute to spreading the disease, but also they are likely to suffer complications therefore contributing to increases in health cost. Currently, there are no drugs available to treat the chronic form of this disease, even though several target targets is the enzyme NADH-fumarate reductase which is present in all stages during the life cycle of T. cruzi but is not present in mammalian cells. In the last few years we have investigated the role of this enzyme utilizing T. brucei procyclic trypomastigotes as a non infective model. We have purified the enzyme, studied its subcellular localization and identified powerful inhibitors that not only block the enzyme in vitro but also inhibit T. brucei procyclic trypomastigotes growth in culture. Several of these inhibitors block the enzyme NADH-fumarate reductase of T. cruzi epimastigotes. We propose to evaluate whether this enzyme constitutes a suitable target to develop an effective chemotherapy against Chagas' disease. The specific aims of this project include: 1) Purification of the enzyme NADH-fumarate reductase from T. cruzi epimastigotes to test inhibitors and determine their potency; 2) evaluation of efficacy of fumarate reductase inhibitors (four of them synthesized in our laboratory and two commercially available) on T. cruzi epimastigotes, trypomastigotes and amastigotes (grown in mammalian cells); 3) Determination of changes in the intracellular concentration of metabolic intermediates (i.e., succinate, fumarate, ATP and NADH) caused by fumarate reductase inhibitors. These experiments will provide important information regarding the enzyme NADH-fumarate reductase as a target against Chagas' disease.
克氏锥虫是南美锥虫病的病原体, 使人丧失能力并且常常是致命的疾病。约1800万人 在中美洲和南美洲都感染了这种寄生虫。虽然 在美国本土感染是非常罕见的,有几个病例 据报告,由于输血或器官移植 移植此外,最近的研究指出,2%(洛杉矶) 洛杉矶)到5%(华盛顿)的拉美裔美国人生活在美国。 感染了不仅这些人可能有助于传播疾病, 但他们也可能遭受并发症, 健康成本的增加。目前,没有药物可用于 治疗这种疾病的慢性形式,即使有几个目标, 目标是酶NADH-延胡索酸还原酶,这是目前在所有 生活史中的各个阶段。cruzi,但不存在于哺乳动物 细胞在过去的几年里,我们研究了这种酶的作用, 利用T.作为非感染性模型的布氏原轮锥鞭毛体。 我们纯化了该酶,研究了其亚细胞定位, 发现了强大的抑制剂,不仅可以在体外阻断酶, 还能抑制T.培养物中布氏原轮锥鞭毛体的生长。 这些抑制剂中的几种阻断辅酶A的NADH-延胡索酸还原酶。 T.克氏上鞭毛体。 我们建议评估这种酶是否 构成了开发有效化疗的合适靶点 对抗南美锥虫病该项目的具体目标包括:1) 从T. cruzi 测试抑制剂并确定其效力; 2) 评价延胡索酸还原酶抑制剂(其中四种 在我们的实验室合成的和两个商业上可获得的)在T. cruzi 上鞭毛体、锥鞭毛体和无鞭毛体(在哺乳动物中生长 3)测定细胞内浓度的变化 代谢中间体(即,琥珀酸盐、富马酸盐、ATP和NADH) 是由延胡索酸还原酶抑制剂引起的这些实验将提供 关于NADH-延胡索酸还原酶作为 针对恰加斯病。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mercaptopyridine-N-oxide, an NADH-fumarate reductase inhibitor, blocks Trypanosoma cruzi growth in culture and in infected myoblasts.
巯基吡啶-N-氧化物是一种 NADH-富马酸还原酶抑制剂,可阻断培养物和感染的成肌细胞中克氏锥虫的生长。
  • DOI:
    10.1111/j.1574-6968.1999.tb13623.x
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Turrens,JF;Newton,CL;Zhong,L;Hernandez,FR;Whitfield,J;Docampo,R
  • 通讯作者:
    Docampo,R
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JULIO F TURRENS其他文献

JULIO F TURRENS的其他文献

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{{ truncateString('JULIO F TURRENS', 18)}}的其他基金

ANALYSIS OF LIGHT EMITTED DURING OXIDATIVE STRESS
氧化应激期间发出的光的分析
  • 批准号:
    6266317
  • 财政年份:
    2001
  • 资助金额:
    $ 10.05万
  • 项目类别:
ROLE OF NADH-FUMARATE REDUCTASE IN TRYPANOSOMA BRUCEI
NADH-富马酸还原酶在布氏锥虫中的作用
  • 批准号:
    2067586
  • 财政年份:
    1992
  • 资助金额:
    $ 10.05万
  • 项目类别:
XANTHINE OXIDASE-MEDIATED INJURY IN ISCHEMIC LIVER
黄嘌呤氧化酶介导的缺血性肝损伤
  • 批准号:
    3240568
  • 财政年份:
    1988
  • 资助金额:
    $ 10.05万
  • 项目类别:
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