Development of plant-derived, resistance-breaking mosquitocides for controlling vectors of Zika virus

项目摘要 黄热病蚊子埃及伊蚊是几种医学上重要的虫媒病毒的主要媒介， 例如寨卡、基孔肯雅热和登革热。蚊媒疾病的控制有赖于使用 针对蚊子神经系统的杀虫剂(如拟除虫菊酯)，以减少蚊子的数量。 然而，蚊子中出现的杀虫剂抗药性降低了这些控制措施的效果。 探员们。因此，需要针对新的分子和生理靶点的新型杀虫剂来美化我们的 病媒控制的化学工具箱。我们最近发现了一种倍半萜二醛 (肉桂，CDIAL)来自马达加斯加一种特有植物的树皮(香桂；科 对雌成虫和幼虫有毒害作用。埃及伊蚊。此外，CDIAL对 Ae对拟除虫菊酯敏感(利物浦)和抗拟除虫菊酯(波多黎各)的代表性菌株。埃及伊蚊， 提示拟除虫菊酯有一种新的作用机制。拟议研究的目标是1) 阐明CDIAL抗Ae的构效关系。埃及伊蚊，以及2)开发天然和合成的 CDIAL的类似物，具有更好的灭蚊效果。AIM 1将使用尖端天然产物药物 开发CDIAL类似物库的发现、生物转化和药物化学方法。目标 2将评估类似物对幼虫和成虫的毒性。埃及伊蚊来自拟除虫菊酯敏感和 拟除虫菊酯抗性菌株。与CDIAL相比，效力更高的类似物将被评估其潜力 用正常细胞系(非洲绿猴)进行体外细胞毒试验的哺乳动物/人类安全性 Vero细胞)。这两个目标的结果将产生不同的天然化合物及其 合成衍生品具有开发成为安全的、抗药性被打破的灭蚊剂的高潜力 控制寨卡、登革热和基孔肯雅病毒的主要传播媒介。

Project Summary The yellow fever mosquito Aedes aegypti is the principal vector of several medically-important arboviruses, such as Zika, chikungunya, and dengue. The control of mosquito-borne diseases relies on the use of insecticides targeting the nervous system of mosquitoes (e.g., pyrethroids) to reduce their populations. However, the emergence of insecticide resistance in mosquitoes has reduced the efficacy of these control agents. Thus, new insecticides targeting novel molecular and physiological targets are needed to embellish our chemical toolbox for vector control. We have recently discovered a drimane sesquiterpene dialdehyde (cinnamodial, CDIAL) from the bark of an endemic plant of Madagascar (Cinnamosma fragrans; family Canellaceae) that is toxic to adult female and larval Ae. aegypti. Moreover, CDIAL is equally toxic to representative pyrethroid-susceptible (Liverpool) and pyrethroid-resistant (Puerto Rico) strains of Ae. aegypti, suggesting a novel mechanism of action from pyrethroids. The goals of the proposed research are to 1) elucidate the structure-toxicity relationship of CDIAL against Ae. aegypti, and 2) develop natural and synthetic analogs of CDIAL with improved efficacy as mosquitocides. Aim 1 will use leading-edge natural product drug discovery, biotransformation, and medicinal chemistry approaches to develop a library of CDIAL analogs. Aim 2 will evaluate the toxicity of the analogs in larval and adult female Ae. aegypti from pyrethroid-susceptible and pyrethroid-resistant strains. Analogs with improved potency compared to CDIAL will be assessed for potential mammalian/human safety using an in vitro cytotoxicity assay with a normal cell line (African green monkey Vero cells). The results from the two aims will yield a diverse collection of natural compounds and their synthetic derivatives that offer high potential for development into safe, resistance-breaking mosquitocides for controlling the primary vector of Zika, dengue, and chikungunya viruses.