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可怕的损失，估计每年有1-2百万人死亡，其中大多数是儿童。用拟除虫菊酯杀虫剂处理过的蚊帐（拟除虫菊酯驱虫蚊帐）是防止疾病传播的第一道防线，但新出现的病媒（冈比亚按蚊）抗药性菌株有可能使这些驱虫蚊帐失效。我们的广泛目标是开发一种新型的乙酰胆碱酯酶（AChE）靶向杀虫剂，用于驱虫蚊帐，使用安全，有效对抗目前的拟除虫菊酯和AChE抗性菌株，并且不太可能促进新的AChE抗性菌株的出现。因此，我们的目标与征集控制疟疾的新干预措施的重点是一致的。2005-2008年FNIH赞助的研究使我们能够在实现长期目标方面取得重大进展。来自NIH的进一步支持将使我们能够建立概念证明，即我们的新型乙酰胆碱酯酶杀虫剂，部署在ITN上，将构成一种上级干预措施来管理疾病媒介。因此，我们的目标也与为转化研究提供资金的征集的既定目标一致。 为了实现我们的目标，我们组建了一个由化学家、结构生物学家、昆虫学家和毒理学家组成的团队。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）选择性氨基甲酸酯的氧化解毒; 2）获得三维结构信息AgAChE，以优化抑制效力和选择性; 3）开发二价氨基甲酸酯的弹性靶点突变; 4）确定战略，以减轻对羧酸酯酶介导的解毒;和5）作出初步评估哺乳动物毒性的最有前途的杀虫剂从这些研究中出现。为了指导我们完成拟议的五年研究，我们准备了一个详细的时间轴和决策树，其中包括五个综合的杀虫剂发现流，以优化田间性能和人类安全。此外，化学合成途径和优化方法的内在互补性（例如对靶位点和代谢抗性机制的适应性）意味着一个流程中的意外困难不需要减缓其他流程中的进展。这些方法增加了项目成功的可能性。 疟疾在撒哈拉以南非洲造成了可怕的损失，目前对抗这种疾病的蚊子媒介的第一道防线是由杀虫剂处理过的蚊帐（ITNs）提供的。然而，对蚊帐上使用的杀虫剂的抗药性不断增加，有可能使这种保护无效。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，对目前的抗药性蚊子有效，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.