Lead optimization and target identification of drugs targeting hypnozoites

项目总结/摘要 该提案的目标是优化治疗复发性疟疾的新铅系列 由间日疟原虫引起当被感染的蚊子叮咬后，她会接种子孢子， 侵入肝细胞。在肝细胞内，这些形式可以发育和繁殖， 休眠这些休眠的催眠虫是持续数周至数年的形式， 可以重新激活导致疾病。没有安全的治疗催眠虫的好药物， 特别是对于葡萄糖-6磷酸脱氢酶缺乏的人。在这个项目中，我将使用一个 新的肝脏阶段培养系统，以推动新电极导线的药物化学优化 具有抗催眠作用的系列药物。第二，我们的目标是利用领先优势， 系列开发化学探针，以确定催眠虫杀死的目标。在那里， 还没有有效的靶点来发现抗催眠虫的药物。最后，我们的目标是使用 结合化学生物学、先进的培养技术和新的代谢标记 方法来验证新的铅和g肝阶段培养模型。

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to optimize a new lead series for treatment of relapsing malaria caused by Plasmodium vivax. When an infectived mosquito bits she inoculates sporozoites that invade hepatocytes. Within the hepatocyte the forms can either develop and reproduce or become dormant. These dormant hypnozoites are the forms that persist for weeks to years and can reactivate to cause disease. There are no good drugs for treating hypnozoites that are safe, especially for glucose-6phosphate dehtdriogenase deficient people. In this project wi wil use a novel liver stage culture system to drive the medicinal chemistry optimization of the new lead series of drugs with anti-hypnozoite activity. Secondly we aim to use the lead and back up series to develop chemical probes to identify the targets for hypnozoite killing. Cyrrently there are no validated targets for drug discovery against hypnozoites. Finally we aim to use a combination of chemical biology, advanced culture techniques, and new metabolic labelling approaches to validate the new leads and gthe liver stage culture model.