Targeting P. falciparum gametocytes for drug development

描述（由申请人提供）：疟疾是一种热带寄生虫病，仍然是一个全球性的健康问题，每年造成约2.8亿人死亡和2.5亿例病例。在过去十年中，扩大的控制和治疗方案降低了疟疾的发病率，并导致呼吁努力消除，甚至可能根除疟疾。这么做 需要针对寄生虫的性阶段采取新的战略，因为性阶段是疾病传播的原因。目前推荐的疟疾化疗不能有效杀死成熟的配子体，使疟疾在无性寄生虫清除后仍能传播一周以上。以前的药物筛选使用仅检测无性复制的测定，因此不监测对配子体的活性。我们最近开发了一种杀配子试验，可用于筛选早期和晚期配子体。该探索性R21提案的目标是双重的：1）分析最近在高通量筛选中发现的杀死无性寄生虫的新型化合物的杀配子体活性，以及2）通过筛选具有已知靶标的杀配子体活性抑制剂文库来鉴定对于配子体繁殖和扩散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，以及推进我们对配子体代谢的理解，并促进有效控制策略的设计。

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.