Discovery of chemically validated malaria liver stage targets

发现经过化学验证的疟疾肝脏阶段目标

• 批准号: 8646859
• 负责人: Elizabeth A Winzeler
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-06 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646859
• 关键词: ATP phosphohydrolase; Alleles; Antibiotic Resistance; Antimalarials; Artemisinins; Awareness; Biological Assay; Biological Availability; Biology; Blood; CD81 gene; Cell Line; Cells; Chemicals; Clinical; Clinical Trials; Combined Modality Therapy; Communities; Confocal Microscopy; Culicidae; Data; Development; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Engineering; Equation; Funding; Genes; Genome; Genome Scan; Goals; Hepatic; Hepatocyte; Human; Immunoelectron Microscopy; In Vitro; Infection; Knock-out; Lead; Licensing; Life Cycle Stages; Liver; Malaria; Medicine; Modeling; Mus; Mutation; Oral; Orthologous Gene; Parasite resistance; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Preclinical Drug Evaluation; Primaquine; Property; Proteins; Resistance; Rodent; Role; Series; Sodium; Sporozoites; Staging; Symptoms; Testing; Tissues; Toxic effect; United States National Institutes of Health; Vivax Malaria; Work; World Health; artemisinine; base; cellular targeting; chemical genetics; design; drug candidate; drug development; genome sequencing; hydrogen transport; improved; in vivo; induced pluripotent stem cell; insight; interest; killings; member; multidisciplinary; pathogen; pressure; prevent; protein protein interaction; public health relevance; research study; response; screening; small molecule; transmission process

DESCRIPTION (provided by applicant): Because blood stage infections produce most clinical manifestations of malaria, drug development has primarily focused on the development of schizonticides targeting Plasmodium falciparum, the causative agent of the most severe form of human malaria. Increased funding and a growing awareness of the problem of parasite resistance have helped to push a number of new schizonticides into the developmental pipeline and even clinical trials. On the other hand, few of these drug candidates are effective against malaria exoerythrocytic stages, and even fewer are likely to provide a radical cure for P. vivax malaria. The need for drugs which can act as a replacement for primaquine is even more urgent as malaria eradication becomes a higher priority for the world health community. In order to stimulate drug development activity against hepatic stages, more work is needed to understand hepatic stage biology and to discover targets whose activity is essential for both hepatic and blood stage development. I will use a chemical genetic approach to investigate pathways that are critically essential to both blood and hepatic parasite development and then characterize the target(s) revealed by this approach. Specifically, I will grow parasites under sub-lethal concentrations of small molecules with activity against blood and hepatic stage parasites until the parasites acquire low level resistance to the small molecules. I will use genome-scanning to determine the likely target(s). Mutations will be engineered into sensitive parasite strains to prove that they cause resistance. Likely targets will be further characterized using immuno and electron microscopy and localization studies, as well as disruption studies. The work may lead to a better understanding of how to treat tissue stage malaria, provide new antibiotic resistance genes, and provide information about how eukaryotic pathogens become resistant to drugs.

描述（由申请人提供）：由于血液阶段感染会产生疟疾的大多数临床表现，因此药物开发主要集中于开发针对恶性疟原虫的裂殖剂，恶性疟原虫是最严重的人类疟疾的病原体。资金的增加和对寄生虫抗药性问题的日益认识有助于将许多新的杀裂殖剂推入开发渠道甚至临床试验。另一方面，这些候选药物中很少有能够有效对抗红细胞外期疟疾的，能够根治间日疟原虫疟疾的药物就更少了。随着消灭疟疾成为世界卫生组织的首要任务，对能够替代伯氨喹的药物的需求变得更加迫切。为了刺激针对肝阶段的药物开发活动，需要做更多的工作来了解肝阶段生物学并发现其活性对于肝阶段和血液阶段开发都至关重要的靶标。我将使用化学遗传学方法来研究对血液和肝脏寄生虫发育至关重要的途径，然后表征该方法揭示的目标。具体来说，我将在亚致死浓度的小分子下培养寄生虫，这些小分子具有抗血液和肝期寄生虫的活性，直到寄生虫获得对小分子的低水平抵抗力。我将使用基因组扫描来确定可能的目标。突变将被设计到敏感的寄生虫菌株中，以证明它们会产生耐药性。将使用免疫和电子显微镜、定位研究以及破坏研究进一步表征可能的目标。这项工作可能会让人们更好地了解如何治疗组织阶段疟疾，提供新的抗生素抗性基因，并提供有关真核病原体如何对药物产生抗药性的信息。