REVERSED SIDEROPHORES AS ANTIMALARIAL AGENTS

反向铁载体作为抗疟剂

基本信息

批准号：
2657786
负责人：
ZVI IOAV CABANTCHIK
金额：
$ 16.31万
依托单位：
HEBREW UNIVERSITY OF JERUSALEM
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-09-01 至 1999-09-28
项目状态：
已结题

项目摘要

Global spread of malaria and resurgence of drug resistant parasites in various regions of the world has created an urgent need for novel chemotherapies. The goal of malaria chemotherapy in general, and of this proposal in particular, is two fold: to selectively affect infected cells with minimal damage to the host organism and to eliminate parasites, including those of highest drug resistance nature. The means by which this goal is meant to be accomplished comprises synthesis and evaluation of novel agents as well as assessment of their mode of action. Two concepts developed in the participating laboratories provide the basis of the proposal: a. selective targeting of drugs based on differential permeation (the ostensible differences in permeation properties of P. falciparum infected red blood cells previously characterized in biophysical terms, serve here as the main route for drug access into infected cells and b. drug design based on a biomimetic approach of iron(III) chelation and modular building for optimizing drug properties (biochemical and pharmacological). The novel drugs are iron carriers based on both ferrichrome and ferrioxamine which are synthesized with requisite hydrophobicity and/or dimensions so as to exert differential deprivation of intracellular iron (III) pools. Novel agents tested for their ability (dose and speed of action) to arrest in vivo parasite growth including drug resistant P. falciparum strains and to arrest in vivo growth in model rodent animals,provided ample support for the feasibility of all the proposed approaches. The additional rationale on which the work lies, is that unlike cells of the mammalian organism which can demonstrably withstand temporary iron deprivation (chelator treatment) regimes and can fully recover from them, intracellular parasites apparently can not. Support for that hypothesis encompasses: modular drug design of traceable (fluorescent and radioactive) forms of chelators with variable size and hydrophobicities and their application for time-resolved tracing of drug permeation into parasitized cells (at various developmental stages), for compartmental drug distribution, for identification of putative biochemical targets (activities associated with iron containing enzymes and parasite-derived endogenous iron(III) shuttles/ carriers) and for assessment of iron acquisition paths in parasitized cells. The project is meant to provide both scientific and applicative grounds for alternative or supplemental chemotherapy for a disease whose eradication is still considered a major health target for mankind.

疟疾的全球传播和抗药性寄生虫在世界各个地区都迫切需要新颖化学疗法。疟疾化学疗法的目的一般是尤其是提案，是两个方面：选择性影响感染的细胞对宿主生物的损害最小并消除寄生虫，包括具有最高耐药性的那些。这是这样的手段目标是要完成的，包括合成和评估新颖的代理商以及对其作用方式的评估。两个概念在参与实验室中开发的提供了提案：基于差渗透的药物选择性靶向（恶性疟原虫的渗透特性的表面差异以前以生物物理术语表征的被感染的红细胞，在这里用作进入感染细胞和b的药物进入的主要途径。基于铁（III）螯合的仿生方法的药物设计和用于优化药物特性的模块化建筑物（生化和药理学）。新型药物是基于两者的铁载体属于必需的属性疏水性和/或尺寸以施加差异性剥夺细胞内铁（III）池。新的代理商测试了他们的能力（剂量和作用速度）在体内寄生虫生长中逮捕耐药性恶性疟原虫菌株并在模型中捕捉体内生长啮齿动物，为所有的可行性提供了充分的支持建议的方法。工作所在的其他理由是与哺乳动物生物体的细胞不同，可以明显地承受暂时的铁剥夺（螯合剂治疗）制度，可以完全从中恢复过来，细胞内寄生虫显然不能。对该假设的支持包括：可追溯的模块化药物设计（荧光和放射性的）螯合剂的形式，其大小可变和疏水性及其用于时间分辨的药物追踪渗透到寄生的细胞（在各个发育阶段），因为隔室药物分布，用于识别推定的生化靶标（与含铁酶有关的活性和寄生虫衍生的内源铁（III）班车/携带者），用于评估寄生细胞中铁的采集路径。该项目旨在提供科学和应用理由用于疾病的替代或补充化疗根除仍然被认为是人类的主要健康目标。