Lead optimization and target identification of drugs targeting hypnozoites

催眠药物的先导化合物优化和靶点识别

• 批准号: 10035076
• 负责人: DENNIS E KYLE
• 金额: $ 70.22万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10035076
• 关键词: Aminoquinolines; Back; Biological Assay; Biological Availability; Biological Models; Biology; Blood; Chemicals; Country; Culicidae; Culture Techniques; Data; Development; Disease; Drug Combinations; Drug Screening; Drug Targeting; Erythrocytes; Evaluation; Evolution; Glucose; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Goals; Harvest; Hemolysis; Hepatocyte; Homologous Gene; Human; Image; In Vitro; Infection; Invaded; Ionophores; Knowledge; Label; Lead; Liver; Malaria; Metabolic; Metabolic Marker; Metabolism; Methods; Modeling; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmodium falciparum; Plasmodium ovale; Plasmodium vivax; Primaquine; Property; Publishing; Relapse; Resistance; Series; Sporozoites; System; Time; Validation; Vivax Malaria; Work; analog; asexual; drug discovery; early screening; high throughput screening; improved; in vitro Model; in vitro activity; lead optimization; lead series; new therapeutic target; nonhuman primate; novel; novel therapeutics; pyridine; quinoline; tool; transmission process

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.

项目摘要/摘要 这项提议的目标是优化治疗复发疟疾的新的铅系列 由间日疟原虫引起。当被感染的蚊子叮咬时，她会接种子孢子 侵入肝细胞。在肝细胞内，这些形式可以发展和繁殖，或者 进入休眠状态。这些休眠的催眠虫是持续数周至数年的形式， 可以重新激活以致病。没有安全的治疗催眠症的良药， 尤其是葡萄糖-6磷酸脱氢酶缺乏者。在这个项目中，我将使用 新型肝期培养体系带动新药化学优化 具有抗催产素活性的系列药物。其次，我们的目标是利用领先地位和后备力量 开发化学探针系列，以识别催眠药的杀灭目标。目前在那里 都不是针对催眠动物的药物发现的有效目标。最后，我们的目标是使用 化学生物学、先进的培养技术和新的代谢标记的结合 验证新的Lead和肝期培养模型的方法。