Use of Transporters to Selectively Deliver Agents to Trypanosomes

人类非洲锥虫病（HAT），通常称为昏睡病，在撒哈拉以南非洲流行，除非治疗，否则不可避免地致命。它是由单细胞寄生虫引起的，寄生虫生活在血液中，最终侵入大脑。目前可用于治疗该疾病的药物不令人满意，这是由于诸如毒性、耐药性、给药困难、缺乏疗效和成本等问题。在这个基础科学提案中，我们的目标是开始开发新药。引起HAT的寄生虫需要人类宿主的营养才能生存。为了吸收这些营养物质，它们的细胞膜中有转运蛋白。其中一些转运蛋白与人类细胞膜中发现的转运蛋白非常不同。一种特殊的转运蛋白，通常参与将重要的化学物质嘌呤运送到细胞中，可以被欺骗携带其他类型的分子（转运蛋白基序），这些分子不被哺乳动物嘌呤转运蛋白携带。我们的目标是通过将杀死寄生虫的化合物附着到这些转运蛋白基序上来开发治疗HAT的新型药物。然后这些化合物应该选择性地杀死寄生虫。该项目将包括这些化合物的设计和制备，评估和研究化合物如何工作。

Human African trypanosomiasis (HAT), more commonly known as sleeping sickness is prevalent in sub-Saharan Africa and is inevitably fatal unless treated. It is caused by single-celled parasites, which live in the blood stream and eventually invade the brain. The current drugs available to treat the disease are unsatisfactory, due to issues such as toxicity, resistance, difficulty in administration of the drugs, lack of efficacy and cost. In this basic science proposal we aim to start the development of new drugs. The parasites which cause HAT require nutrients from the human host for their survival. To take up these nutrients, they have transporters in their cell membranes. Some of these transporters are very different from those found in human cell membranes. One particular transporter, usually involved in carrying important chemicals called purines into cells, can be tricked into carrying other classes of molecules (transporter motifs), which are not carried by mammalian purine transporters. We aim to develop new classes of drugs to treat HAT by attaching compounds that will kill parasites to these transporter motifs. These compounds should then selectively kill the parasites. The project will consist of design and preparation of these compounds, evaluation and studying how the compounds work.