Trypanosomatid protein synthesis as a target for novel drug therapies

锥虫是一种在昆虫媒介和哺乳动物宿主之间迁移的真核寄生虫。它们引起许多高度衰弱和可能致命的人畜共患疾病，在全球范围内对人类健康（和寿命）产生重大影响。导致恰加斯病的克氏锥虫据信影响了墨西哥、中美洲和南美洲约1100万人。目前还没有针对恰加斯病的疫苗，现有的抗寄生虫治疗方法令人不快，也不是完全有效。此外，对常用的唑类和硝基衍生物药物的耐药性正在上升。利什曼原虫通过白蛉在南美洲、南欧、中东、亚洲和非洲传播，在大约1200万人中引起三种疾病（皮肤、粘膜和内脏利什曼病）。许多用于治疗利什曼原虫的药物都有副作用，而且耐药性正在增加。在本项目中，我们建议探索开发有效对抗这些危险寄生虫的药物的新途径的可行性。这一途径涉及对寄生虫中蛋白质合成机制的不同靶向，以使人类（或动物）宿主不受影响。在这个项目的两年里，我们希望对锥虫病药物的重要靶点有一个显著的了解，并确定一些候选药物，这些药物可以在本研究之后纳入动物试验。

Trypanosomatids are eukaryotic parasites that migrate between insect vectors and mammalian hosts. They cause a number of highly debilitating and potentially fatal zoonotic diseases with major impacts on human health (and life-span) on a global scale. Trypanosoma cruzi, which causes Chagas disease, is believed to affect approximately 11 million people in Mexico, Central America and South America. There is currently no vaccine against Chagas disease, and the available antiparasitic treatments are unpleasant and not fully effective. Moreover, resistance to the commonly used azole- and nitro- derivative drugs is rising. Leishmania is spread by sandflies in South America, southern Europe, the Middle East, Asia and Africa, and causes three types of disease (cutaneous, mucocutaneous and visceral leishmaniasis) in approximately 12 million people. Many of the drugs used against Leishmania have side effects, and resistance is on the increase. In this project, we propose to investigate the feasibility of pursuing a new route to developing drugs effective against these dangerous parasites. This route involves differential targeting of the protein synthesis machinery in the parasite so that the human (or animal) host is unaffected.Over the two years of this project we expect to achieve a significantly enhanced level of understanding of important targets for drugs in trypanosomatids and also to have identified some candidate drugs that can be incorporated into trials in animals subsequent to this study.