TRYPANOSOMIASIS CHEMOTHERAPY BY GLYCOLYSIS INHIBITION

研究计划摘要：我们已经确定了一种理性的方法来 非洲锥虫病的化疗依赖于 同时抑制两条平行的代谢途径，这两条途径 对于寄生虫的能源生产是必不可少的。首先，有一个 异常的线粒体电子传递系统(甘油磷酸 与主要的糖酵解途径有关。这可以 可被水杨基异羟肟酸(SHAM)阻断。当后者被阻止时， 锥虫转移到另一条糖酵解途径，从而产生 甘油。这种替代途径可以通过外源供应来阻断 甘油。尽管这些药物具有特殊性，而且事实是 假手术加甘油可治愈实验动物，其毒性 治疗剂量的假药限制了这种药物的实际效用 组合。我们建议将这种方法发展成一种有用的 化疗方案。我们的初步研究表明，有几个 不同类型的化合物可以抑制易受假手术影响的糖酵解途径。 因此，我们将通过合成类似物来追踪这些线索 含有被认为能增强活性的官能团。这些化合物将会 使用两种检测程序进行体外筛选。首先，我们将确定 这些化合物抑制人的独特呼吸系统的能力 寄生虫。然后我们将用抑制剂+孵化完整的寄生虫 甘油混合物，并测试其在新鲜动物身上的传染性。什么时候 有希望的抑制剂已经被确定，我们将评估他们的急性 毒性，单独或与甘油一起。药代动力学研究 然后进行单独的抑制剂和联合使用 从而确定甘油在体内的有效剂量方案。最后，在 活体研究将在受感染的动物身上进行。这些活体研究 将在适当的时候包括该疾病的小鼠中枢神经系统模型。

Abstract of Research Plan: We have identified a rational approach to chemotherapy for African trypanosomiasis which depends upon the simultaneous inhibition of two parallel metabolic pathways which are essential for energy production by the parasites. First, there is an unusual mitochondrial electron transport system (the glycerophosphate oxidase system) associated with the primary glycolytic pathway. This can be blocked by salicylhydroxamic acid (SHAM). When the latter is blocked, the trypanosomes shift to another glycolytic pathway which produces glycerol. This alternate pathway can be blocked by exogenously supplied glycerol. Despite the specificity of these agents and the fact that combining SHAM and glycerol can cure experimental animals, the toxicity of SHAM at curative doses limits the practical utility of this drug combination. We propose to develop this approach into a useful chemotherapeutic regimen. Our preliminary studies have shown that several types of compounds can inhibit the glycolytic pathway susceptible to SHAM. Accordingly, we will pursue these leads via synthesis of analogues which contain functional groups believed to enhance activity. The compounds will be screened in vitro using two assay procedures. First, we will determine the ability of the compounds to inhibit the unique respiratory system of the parasites. Then we will incubate intact parasites with inhibitor + glycerol combinations and test their infectivity in fresh animals. When promising inhibitors have been identified, we will evaluate their acute toxicity, both alone and together with glycerol. Pharmacokinetic studies will then be conducted, both of the inhibitor alone and in combination with glycerol so as to determine an effective dose regimen in vivo. Finally, in vivo studies will be performed in infected animals. These in vivo studies will include, when appropriate, a mouse CNS model of the disease.