Development of small molecule mosquitocides for controlling the primary vector of Zika virus, Aedes aegypti

项目摘要 埃及伊蚊是寨卡病毒和其他几种重要医学病毒的主要媒介 虫媒病毒，如基孔肯雅热和登革热。目前，控制蚊媒传播的努力 疾病在很大程度上依赖于使用针对神经系统的杀虫剂(如拟除虫菊酯) 以减少蚊子的数量。然而，在中国出现了抗药性。 蚊子正在降低这些控制剂的效力。因此，新的杀虫剂具有新颖的 行动机制是必要的。我们之前已经证明了1)内向整流器 钾(KIR)通道在蚊子的排泄和繁殖中起着基本的作用， 2)蚊虫KIR通道的小分子抑制剂对蚊子有毒性作用。 因此，KIR通道是开发新型杀虫剂的有用分子靶点。 行动机制。拟议的工作旨在开发KIR的小分子抑制剂 进入对人类有名义影响的抗药性杀蚊剂的渠道 和蜜蜂(Apis Melvena)。AIM 1将使用尖端药物发现方法来 开发Ae的3种抑制剂的类似物。Aegypti Kir1频道(AeKir1)展示热门话题 对蚊子的毒性。我们将确定有效抑制AeKir1的类似物，但不抑制AeKir1 人KIR通道和蜜蜂KIR1通道的体外实验。AIM 2将在体内利用 毒理学检测：1)对拟除虫菊酯敏感和抗性的成年雌性Ae。埃及伊蚊 2)成年蜜蜂评估毒性、抗药性潜力和种类-- 类似物的选择性。此外，这些类似物将在体外进行放射性配基结合测试。 评估它们与高度优先的哺乳动物非靶标的相互作用，从而评估它们的 潜在的人体毒性。综合起来，这两个目标的结果将产生不同的 收集有效的和选择性的AeKir1抑制剂类似物，并鉴定那些表现出 最有潜力开发成控制初级蚊虫的新型安全灭蚊剂 寨卡、登革热和基孔肯雅病毒的传播媒介。

Project Summary Aedes aegypti is the principal vector of Zika virus and several other medically-important arboviruses, such as chikungunya and dengue. Presently, efforts to control mosquito-borne diseases rely heavily on the use of insecticides targeting the nervous system (e.g., pyrethroids) to reduce mosquito populations. However, the emergence of insecticide resistance in mosquitoes is reducing the efficacy of these control agents. Thus, new insecticides with novel mechanisms of action are needed. We have previously demonstrated that 1) inward-rectifier potassium (Kir) channels perform fundamental roles in mosquito excretion and reproduction, and 2) small-molecule inhibitors of mosquito Kir channels elicit toxic effects on mosquitoes. Thus, Kir channels represent useful molecular targets for developing insecticides with novel mechanisms of action. The proposed work aims to develop small molecule inhibitors of Kir channels into resistance-breaking mosquitocides that would have nominal effects on humans and honey bees (Apis mellifera). Aim 1 will use leading-edge drug discovery approaches to develop analogs of 3 inhibitors of the Ae. aegypti Kir1 channel (AeKir1) that exhibit topical toxicity on mosquitoes. We will identify analogs that potently inhibit AeKir1, but do not inhibit a panel of human Kir channels and the honey bee Kir1 channel in vitro. Aim 2 will utilize in vivo toxicology assays in 1) pyrethroid-susceptible and pyrethroid-resistant adult female Ae. aegypti and 2) adult honey bees to evaluate the toxicity, resistance-breaking potential, and species- selectivity of the analogs. Moreover, the analogs will be tested in vitro with radioligand binding assays to assess their interactions with high-priority mammalian off-targets and thereby their potential human toxicity. Taken together, the results from the two aims will yield a diverse collection of potent and selective AeKir1 inhibitor analogs and identify those that exhibit the greatest potential for development into novel, safe mosquitocides for controlling the primary vector of Zika, dengue, and chikungunya viruses.