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医学上重要的病毒的主要载体。 虫媒病毒，如基孔肯雅病毒和登革热。目前，控制蚊子传播的努力 疾病严重依赖于使用靶向神经系统的杀虫剂（例如，拟除虫菊酯） 来减少蚊子的数量。然而，杀虫剂抗药性的出现， 蚊子正在降低这些控制剂的效力。因此，具有新的 需要行动机制。我们以前已经证明，1）内向整流器 钾（Kir）通道在蚊子排泄和繁殖中起着重要作用， 和2）蚊子Kir通道的小分子抑制剂引起对蚊子的毒性作用。 因此，Kir通道代表了用于开发具有新的杀昆虫剂的有用的分子靶标。 行动机制。这项工作旨在开发Kir的小分子抑制剂 进入对人类有轻微影响的破坏抗药性的灭蚊剂 蜜蜂（Apis mellifera）Aim 1将使用领先的药物发现方法， 开发Ae的3种抑制剂的类似物。埃及Kir 1通道（AeKir 1）， 对蚊子的毒性。我们将鉴定有效抑制AeKir 1但不抑制AeKir 1的类似物。 体外人Kir通道和蜜蜂Kir 1通道的面板。Aim 2将在体内使用 在1）拟除虫菊酯敏感和拟除虫菊酯抗性成年雌性Ae. aegypti 和2）成年蜜蜂，以评估毒性、抗性破坏潜力和物种- 类似物的选择性。此外，将在体外用放射性配体结合测试类似物 用于评估它们与高优先级哺乳动物脱靶的相互作用的测定， 潜在的人体毒性。两者结合起来，这两个目标的结果将产生一个多样化的 收集有效的和选择性的AeKir 1抑制剂类似物，并鉴定那些表现出 最大的潜力，发展成为新的，安全的灭蚊剂，以控制主要 寨卡病毒、登革热病毒和基孔肯雅病毒的载体。

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.