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: 10455026
• 负责人: DENNIS E KYLE
• 金额: $ 66.16万
• 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/10455026
• 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; Persons; 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.

项目概要/摘要 该提案的目标是优化治疗复发性疟疾的新先导药物系列 由间日疟原虫引起。当受感染的蚊子叮咬时，她会接种子孢子， 侵入肝细胞。在肝细胞内，这些形式可以发育和繁殖，或者 进入休眠状态。这些休眠子的形式可以持续数周至数年，并且 可以重新激活导致疾病。目前尚无安全有效的治疗休眠子的良药， 特别适合葡萄糖-6磷酸脱氢酶缺乏的人。在这个项目中我们将使用 新型肝阶段培养系统驱动新先导药物化学优化 系列具有抗催眠活性的药物。其次，我们的目标是使用主力和后援 系列开发化学探针来识别催眠杀灭的目标。当前在那里 没有针对催眠子的药物发现的经过验证的目标。最后我们的目标是使用一个 化学生物学、先进培养技术和新代谢标记的结合 验证新线索和肝脏阶段培养模型的方法。