Development of vector-specific, resistance-breaking insecticides to reduce malari

描述(申请人提供)：疟疾在撒哈拉以南非洲造成了可怕的伤亡，估计每年有100-200万人死亡，其中大部分是儿童。拟除虫菊酯杀虫剂处理的蚊帐(拟除虫菊酯蚊帐)提供了防止疾病传播的第一道防线，但新出现的抗药性病媒(冈比亚按蚊)可能使这些蚊帐无效。我们的主要目标是开发一种新型的乙酰胆碱酯酶(AChE)靶向杀虫剂，用于在ITNS上部署，使用安全，对现有的拟除虫菊酯和AChE抗性菌株有效，并且不太可能促进新的AChE抗性菌株的出现。因此，我们的目标与征集防治疟疾的新干预措施的重点是一致的。2005-2008年由FNIH赞助的研究使我们在实现长期目标方面取得了重大进展。来自NIH的进一步支持将使我们能够建立概念证据，证明我们部署在ITN上的新型AChE杀虫剂将构成管理病媒的更好干预措施。因此，我们的目标也与征集资金资助翻译研究的既定目标一致。 为了实现我们的目标，我们组建了一支由化学家、结构生物学家、昆虫学家和毒物学家组成的团队。我们的具体目标是：1)提高AN的稳定性。冈比亚乙酰胆碱酯酶(AgAChE)--选择性氨基甲酸酯类化合物可用于氧化脱毒；2)获得Agache的3D结构信息，以优化抑制效力和选择性；3)开发抗靶点突变的二价氨基甲酸酯；4)确定缓解羧酸酯酶介导的解毒的策略；以及5)对这些研究中出现的最有希望的杀虫剂进行初步评估。为了指导我们完成拟议的五年研究，我们准备了一份详细的时间表和决策树，其中包括五个综合的杀虫剂发现流，以优化田间表现和人类安全。此外，化学合成路线和优化方法的内在互补性(例如，对目标位置和代谢耐受机制的弹性)意味着一个流程中的意外困难不一定会减缓其他流程的进展。这些多重方法增加了项目成功的可能性。 疟疾在撒哈拉以南非洲地区造成了可怕的损失，目前针对这种疾病的蚊媒的第一道防线是由杀虫剂处理蚊帐(ITN)提供的。然而，对蚊帐上使用的杀虫剂类别的抗药性日益增长，可能会使这种保护无效。我们建议开发一种新的杀虫剂，这种杀虫剂对ITN的部署是安全的，对现有的抗药性蚊子有效，而且不太可能促进新的抗药性菌株的出现。

DESCRIPTION (provided by applicant): Malaria exacts a terrible toll in sub-Saharan Africa, killing an estimated 1-2 million persons each year, mostly children. Pyrethroid-based insecticide treated nets (pyrethroid ITNs) provide the first line of defense against disease transmission, but emerging resistant strains of the disease vector (Anopheles gambiae) threaten to render these ITNs ineffective. Our broad objective is to develop a new class of acetylcholinesterase (AChE)-targeting insecticide for deployment on ITNs, that is safe for use, effective against current pyrethroid- and AChE- resistant strains, and is less likely to foster emergence of new AChE-resistant strains. Thus our goal is consistent with the focus of the solicitation on novel interventions for the control of Malaria. FNIH-sponsored research from 2005-2008 enabled us to make significant progress towards our long-term goal. Further support from NIH will allow us to establish proof of concept that our novel AChE-based insecticide, deployed on an ITN, would constitute a superior intervention to manage the disease vector. Thus our goal is also consistent with the stated aim of the solicitation to fund translational research. To achieve our goal we have assembled a team of chemists, structural biologists, entomologists, and toxicologists. Our specific aims are to 1)improve stability of An. gambiae AChE (AgAChE)-selective carbamates to oxidative detoxification; 2)acquire 3D structural information on AgAChE to optimize inhibition potency and selectivity; 3)develop bivalent carbamates for resilience to target-site mutation; 4)identify strategies to mitigate against carboxylesterase-mediated detoxification; and 5)make a preliminary assessment of mammalian toxicity of the most promising insecticides to emerge from these studies. To guide us through the proposed five years of research we have prepared a detailed timeline and decision tree that incorporate five integrated streams of insecticide discovery for optimizing field performance and human safety. Moreover the built-in complementarity of the chemical synthesis routes and the optimization approaches (e.g. resilience to both target-site and metabolic resistance mechanisms) means that unexpected difficulty in one stream need not slow progress in the other streams. These multiple approaches increase the probability of project success. Malaria exacts a terrible toll in sub-Saharan African, and at present the first line of defense against the mosquito vector of the disease is provided by insecticide treated nets (ITNs). However, growing resistance to the class of insecticide used on the nets threatens to make this protection ineffective. We propose to develop a new class of insecticide that is safe for ITN deployment, effective against current insecticide-resistant mosquitoes, and less likely to promote emergence of new resistant strains.