Targeting P. falciparum gametocytes for drug development

描述(申请人提供)：疟疾是一种热带寄生虫病，仍然是一个全球卫生问题，每年造成约180万人死亡和2.5亿例病例。在过去十年中，扩大的控制和治疗方案减少了这种疾病的发病率，并导致人们呼吁努力消除、甚至可能根除疟疾。要做到这一点 需要针对导致疾病传播的寄生虫的有性阶段制定新的战略。目前推荐的疟疾化疗不能有效杀死成熟的配子体，使疟疾在清除无性寄生虫后传播一周以上。以前的药物筛选使用的分析只检测到无性复制，因此不会监测针对配子细胞的活动。我们最近开发了一种配子细胞杀伤法，可以用来筛选早期和晚期配子体。这个探索性的R21提案的目的有两个：1)分析新近发现的杀死无性寄生虫的新化合物的配子细胞杀灭活性；2)通过筛选具有已知靶点的药理活性抑制剂文库，识别对配子细胞的繁殖和传播至关重要的代谢途径。总之，这些方法应该确定可以作为进一步药物开发目标的化合物类别，以及促进我们对配子体新陈代谢的理解，并促进有效控制策略的设计。 与公共卫生相关：这项研究的长期目标是开发能够阻止疟疾在人与人之间传播的药物。世界上40%的人口生活在疟疾流行地区，常用的抗疟疾药物对导致疾病传播的寄生虫阶段无效。有效减少疟疾传播的药物将降低发病率和死亡率，并有助于消除和根除疟疾的努力。

DESCRIPTION (provided by applicant): Malaria is a tropical parasitological disease that remains a global health problem, causing ~.8 million deaths and 250 million cases annually. Expanded control and treatment programs in the past decade have reduced the incidence of the disease and lead to the call for efforts to eliminate, possibly even eradicate, malaria. To do this new strategies are needed that target the sexual stages of the parasites, which are responsible for disease transmission. The current recommended chemotherapy for malaria does not effectively kill mature gametocytes, allowing malaria to be transmitted for more than a week after the clearance of asexual parasites. Previous drug screens used assays that only detected asexual replication and therefore did not monitor activity against gametocytes. We have recently developed a gametocytocidal assay that can be used to screen against both early and late stage gametocytes. The goal of this exploratory R21 proposal is twofold 1) to analyze to the gametocytocidal activity of novel compounds recently found to kill asexual parasites in a high throughput screen and 2) to identify metabolic pathways that are essential for the propagation and spread of gametocytes by screening a library of pharmacologically active inhibitors with known targets. Together these approaches should identify classes of compounds that can be targeted for further drug development, as well as advance our understanding of gametocyte metabolism and facilitate the design of effective control strategies. PUBLIC HEALTH RELEVANCE: The long term goal of this research is to develop drugs that can block malaria transmission from one person to another. Forty percent of the world's population lives in malaria endemic areas and the commonly used antimalarials are not effective against the stages of the parasite that are responsible for the spread of the disease. Drugs that effectively reduce the transmission of malaria will decrease morbidity and mortality, as well as contribute to malaria elimination and eradication efforts.