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

基本信息

批准号：
8263021
负责人：
Elizabeth A Winzeler
金额：
$ 38.73万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/8263021
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 Delivery Systems Drug Kinetics 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 Screening procedure 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 small molecule transmission process

项目摘要

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. PUBLIC HEALTH RELEVANCE: Many antimalarial drugs alleviate symptoms but do not necessarily result in a complete cure because some malaria parasites are able to persist asymptomatically in the liver for months or years. The inability to eliminate cryptic liver forms creates a barrier to malaria eradication. We propose to find new targets that are critical to the liver stages as well as the blood stages with the long term aim of designing better drugs.

描述（由申请人提供）：由于血液阶段感染产生了大多数疟疾的临床表现，因此药物发育主要集中于靶向恶性疟原虫的精神分裂剂的发展，这是最严重的人类疟疾形式的病因。资金增加和对寄生虫耐药性问题的越来越多的意识有助于将许多新的精神分裂症推向发育管道甚至临床试验。另一方面，这些候选药物中很少有有效防止疟疾外鞭毛细胞阶段有效，甚至很少有可能为维瓦克斯疟疾提供根本治疗。由于消除疟疾成为世界卫生社区的优先事项，因此对可以替代primaquine的药物的需求更加紧迫。为了刺激针对肝阶段的药物发育活动，需要更多的工作来了解肝阶段生物学，并发现其活性对于肝和血液阶段发育至关重要的靶标。我将使用一种化学遗传方法来研究对血液和肝寄生虫发育至关重要的途径，然后表征该方法所揭示的靶标。具体而言，我将在小分子的亚致死浓度下种植寄生虫，其活性抗血液和肝寄生虫，直到寄生虫获得对小分子的低水平耐药性。我将使用基因组扫描来确定可能的目标。突变将被设计为敏感的寄生虫菌株，以证明它们会引起抗性。可能会通过免疫和电子显微镜和定位研究以及破坏研究进一步表征目标。这项工作可能会更好地理解如何治疗组织阶段疟疾，提供新的抗生素耐药性基因，并提供有关真核病原体如何对药物具有抵抗力的信息。公共卫生相关性：许多抗疟药减轻了症状，但不一定会导致完全治愈，因为某些疟疾寄生虫能够在肝脏中持续存在数月或几年。无法消除神秘的肝脏形式会造成消除疟疾的障碍。我们建议找到对肝脏阶段至关重要的新目标以及血液阶段，其长期目的是设计更好的药物。