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

开发植物源性杀蚊剂来控制寨卡病毒载体

• 批准号: 9291272
• 负责人: Peter M Piermarini
• 金额: $ 19.31万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291272
• 关键词: Acetylcholine; Adult; Aedes; Agriculture; Arboviruses; Biological Assay; Cell Line; Cercopithecus pygerythrus; Chemicals; Chikungunya virus; Chrysanthemum; Collection; Culicidae; Dengue; Dengue Virus; Development; Dimerization; Disease; Enzymes; Exhibits; Family; Female; Goals; Guillain-Barré Syndrome; Human; In Vitro; Insecta; Insecticide Resistance; Insecticides; Ion Channel; Libraries; Link; Madagascar; Medical; Medicine; Metabolic Biotransformation; Microcephaly; Molecular; Mosquito Control; Mosquito-borne infectious disease; Natural Product Drug; Natural Products; Nervous system structure; Normal Cell; Penicillium; Pest Control; Pharmaceutical Chemistry; Physiological; Plants; Population; Property; Public Health; Puerto Rico; Pyrethrins; Reaction; Research; Resistance; Safety; Sesquiterpenes; Sodium Channel; Source; Spices; Structure; Therapeutic; Toxic effect; United States National Institutes of Health; Vaccines; Vero Cells; Work; Yellow Fever; Zika Virus; analog; chikungunya; cytotoxic; cytotoxicity; dimer; drug discovery; esterase; fungus; improved; kidney cell; mosquitocidal; novel; pathogen; plant growth/development; pyrethroid; resistant strain; response; vector; vector control; vector mosquito; voltage

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.

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载体， 如寨卡病毒、基孔肯雅病毒和登革热。蚊子传播疾病的控制依赖于使用 靶向蚊子神经系统的杀虫剂（例如，拟除虫菊酯），以减少其种群。 然而，蚊子抗药性的出现降低了这些控制的效果 剂.因此，需要靶向新的分子和生理靶标的新杀虫剂来修饰我们的环境。 用于病媒控制的化学工具箱。我们最近发现了一种补身烷倍半萜二醛 （肉桂醛，CDIAL）来自马达加斯加特有植物（肉桂属;科 Canellaceae），对成年雌性和幼虫Ae有毒。埃及人。此外，CDIAL对 代表性的拟除虫菊酯敏感（利物浦）和拟除虫菊酯抗性（波多黎各）菌株。埃及人， 表明拟除虫菊酯的一种新的作用机制。本研究的目的是：（1） 阐明了CDIAL对Ae.埃及，2）开发天然和合成 作为杀蚊剂具有改进功效的CDIAL类似物。目标1将使用领先的天然产物药物 发现、生物转化和药物化学方法来开发CDIAL类似物的文库。目的 2将评估类似物在幼虫和成年雌性Ae中的毒性。埃及伊蚊对拟除虫菊酯敏感， 拟除虫菊酯抗性菌株。将评估与CDIAL相比效价提高的类似物的潜在 使用正常细胞系（非洲绿色猴）进行的体外细胞毒性试验的哺乳动物/人类安全性 Vero细胞）。这两个目标的结果将产生各种各样的天然化合物及其用途。 合成衍生物，为开发安全、破坏抗性的灭蚊剂提供了很大的潜力， 控制寨卡病毒、登革热病毒和基孔肯雅病毒的主要载体。