Trypanosomatid protein synthesis as a target for novel drug therapies

锥虫是在昆虫媒介和哺乳动物宿主之间迁徙的真核寄生虫。在全球范围内，它们会导致一些极具破坏性和潜在致命性的人畜共患病，对人类健康(和寿命)产生重大影响。引起恰加斯病的克氏锥虫据信在墨西哥、中美洲和南美洲影响大约1100万人。目前还没有针对恰加斯病的疫苗，可用的抗寄生虫治疗令人不快，也不是完全有效。此外，对常用的唑类和硝基类药物的耐药性正在上升。利什曼原虫通过沙蝇在南美洲、南欧、中东、亚洲和非洲传播，在大约1200万人中引起三种疾病(皮肤病、粘膜皮肤病和内脏利什曼病)。许多用于治疗利什曼病的药物都有副作用，耐药性正在增加。在这个项目中，我们建议探索一种新的途径来开发有效对抗这些危险寄生虫的药物的可行性。这条路线涉及到对寄生虫中蛋白质合成机制的不同靶向，从而使人类(或动物)宿主不受影响。在这个项目的两年时间里，我们希望对锥虫药物的重要靶点有一个显著的提高，并在这项研究之后确定一些可以纳入动物试验的候选药物。

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.