Developing resistance-breaking insecticides at mosquito muscarinic acetylcholine receptors to reduce malaria transmission

项目摘要/摘要 减少媒介种群将有助于减少蚊媒疾病对全球的影响。过度依赖于 从农业中改变用途的杀虫剂类别已达到广泛抗药性的顶峰，导致了关键的 需要研究能够为杀虫剂开发提供选择性靶标的生理过程。昆虫 M受体(MAChRs)已被证实是一种杀虫剂靶标，但没有分子 这一行动模式目前被用于虫害防治。拟议研究的长期目标是 利用昆虫和哺乳动物之间的药理差异开发mAChR选择性杀虫剂 纳入蚊子控制项目。拟议研究的总体目标是调查 利用化学探针和新型营养物质研究冈比亚按蚊的药理和生理 结合物以增强这些毒物的口服给药。拟议研究的中心假设是 昆虫mAChR亚型显示出独特的药理作用，并在蚊子中枢神经系统中发挥关键作用 系统(CNS)。这项拟议研究的理由是基于蚊子对全球健康造成的负担 实施，重点是疟疾媒介冈比亚按蚊。将执行两个具体目标来测试 中心假说。具体目标#1将询问AN的药理学。冈比亚亚型mAChR使用 具有明确生物学和药学活性的胆碱能化学库。具体目标2将重点放在 合成一系列铅分子类似物以探索蚊子毒碱受体活性的功能， 以及其饮食递送的吸收途径。拟议的研究在概念上是创新的 与现状背道而驰：一)调查毒鼠强系统作为一种未被利用的行动模式 打破对杀虫剂的抗性，以及ii)利用中肠营养转运蛋白来促进膳食中对前体的吸收。 杀虫剂。该项目将在蚊子生物学和杀虫剂领域取得重大进展。 毒理学和发展。

Project Summary/Abstract Reducing vector populations will help decrease the global impact of mosquito-borne diseases. Over reliance on insecticide classes repurposed from agriculture has culminated in widespread resistance, resulting in a critical need to investigate physiological processes that can provide selective targets for insecticide development. Insect muscarinic acetylcholine receptors (mAChRs) have been validated as an insecticide target, but no molecules with this mode of action are currently used for pest control. The long-term goal of the proposed research is to exploit pharmacological differences between insects and mammals to develop mAChR-selective insecticides to be integrated into mosquito control programs. The overall objective of the proposed research is to investigate the pharmacology and physiology of Anopheles gambiae mAChRs using chemical probes and novel nutrient conjugates to enhance oral delivery of these toxicants. The central hypothesis of the proposed research is that insect mAChR subtypes display unique pharmacology and play critical roles in the mosquito central nervous system (CNS). The rationale for the proposed research is based on the global health burden that mosquitoes impose, with a focus on the malarial vector Anopheles gambiae. Two specific aims will be performed to test the central hypothesis. Specific Aim #1 will interrogate the pharmacology of An. gambiae mAChR subtypes using a cholinergic chemical library with defined biological and pharmaceutical activity. Specific Aim #2 will focus on the synthesis of a series of analogs of a lead molecule to probe the function of mosquito muscarinic receptor activity, as well as absorption pathways for its dietary delivery. The proposed research is conceptually innovative as it is a departure from the status quo by i) investigating the muscarinic system as an unexploited mode of action to break insecticide resistance, and ii) leveraging midgut nutrient transporters to facilitate dietary uptake of pro- insecticides. This project will provide significant advances to the fields of mosquito biology, as well as insecticide toxicology and development.