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

开发用于控制寨卡病毒主要载体埃及伊蚊的小分子杀蚊剂

• 批准号: 9386127
• 负责人: Jerod S. Denton
• 金额: $ 25.58万
• 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: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386127
• 关键词: Acetylcholine; Adult; Aedes; Apis; Arboviruses; Area; Bees; Binding; Biological Assay; Chemicals; Chikungunya virus; Collection; Culicidae; Dengue; Dengue Virus; Development; Disease; Dose; Enzymes; Excretory function; Exhibits; Female; G-Protein-Coupled Receptors; Goals; Guillain-Barré Syndrome; Honey; Human; In Vitro; Insecta; Insecticide Resistance; Insecticides; Ion Channel; Lead; Mammals; Medical; Microcephaly; Molecular; Molecular Target; Mosquito Control; Mosquito-borne infectious disease; National Institute of Allergy and Infectious Disease; Nervous system structure; Osmoregulation; Pharmaceutical Chemistry; Physiological; Play; Population; Potassium; Puerto Rico; Reproduction; Research; Resistance; Role; Safety; Series; Sodium Channel; Structure-Activity Relationship; Toxic effect; Toxicology; Work; Yellow Fever; Zika Virus; analog; chikungunya; drug discovery; esterase; high throughput screening; improved; in vitro Assay; in vitro testing; in vivo; inhibitor/antagonist; interest; next generation; novel; pathogen; prototype; pyrethroid; radioligand; resistant strain; screening; small molecule; small molecule inhibitor; vector; vector control

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.

项目摘要 埃及埃及是寨卡病毒的主要媒介，还有其他几种医学上的媒介 Arboviruses，例如Chikungunya和登革热病毒。目前，控制蚊子出生的努力 疾病严重依赖于针对神经系统的杀虫剂的使用（例如拟除虫菊酯） 减少蚊子种群。但是，在 蚊子正在降低这些对照剂的功效。因此，新的杀虫剂与新颖 需要作用机理。我们以前已经证明1）向内旋转器 钾（KIR）通道在蚊子排泄和繁殖中扮演基本角色， 2）蚊子通道的小分子抑制剂会引起对蚊子的毒性作用。 因此，KIR通道代表有用的分子靶标，用于开发新型杀虫剂 作用机理。提出的工作旨在开发KIR的小分子抑制剂 通道进入抗性造驱肽，对人类有名义影响 和蜜蜂（Apis Mellifera）。 AIM 1将使用领先的药物发现方法 开发3个AE抑制剂的类似物。展示主题的Aegypti Kir1频道（AEKIR1） 蚊子的毒性。我们将确定有效抑制Aekir1但不抑制A的类似物 人类KIR通道和蜜蜂KIR1通道的体外面板。 AIM 2将使用体内 毒理学测定1）拟除虫菊酯敏感和抗多甲虫素耐药的成年雌性AE。埃及 2）成年蜜蜂评估毒性，破坏性潜力和物种 - 类似物的选择性。此外，类似物将在放射性结合的体外测试 评估他们与高优势哺乳动物脱离目标的互动的测定，从而 潜在的人类毒性。综上所述，两个目标的结果将产生多种多样的 收集有效和选择性的AEKIR1抑制剂类似物，并识别出表现出的抑制剂 开发成新颖的，安全蚊子的最大潜力，用于控制主要 Zika，登革热和基孔肯雅病毒的载体。