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

项目总结/摘要 减少病媒种群将有助于减少蚊媒疾病的全球影响。过度依赖 从农业中重新利用的杀虫剂种类导致了广泛的耐药性，导致了严重的 需要调查生理过程，可以提供杀虫剂的发展选择性目标。昆虫 毒蕈碱乙酰胆碱受体（mAChRs）已被证实为杀虫剂靶标，但没有分子 目前用于害虫防治。拟议研究的长期目标是 利用昆虫和哺乳动物之间的药理学差异，开发mAChR选择性杀虫剂， 将其纳入蚊子控制计划。本研究的总体目标是调查 应用化学探针和新营养素研究冈比亚按蚊mAChRs药理学和生理学 偶联物以增强这些毒物的口服递送。这项研究的中心假设是， 昆虫mAChR亚型具有独特的药理作用，在蚊虫中枢神经系统中发挥重要作用 系统（CNS）。这项研究的基本原理是基于蚊子对全球健康造成的负担， 重点是疟疾病媒冈比亚按蚊。将执行两个具体目标来测试 中心假设具体目标#1将询问An的药理学。冈比亚mAChR亚型， 具有确定的生物和药物活性的胆碱能化学文库。具体目标#2将侧重于 合成一系列先导分子的类似物以探测蚊子毒蕈碱受体活性的功能， 以及其饮食递送的吸收途径。拟议的研究是概念创新，因为它是 通过i）调查毒蕈碱系统作为一种未开发的作用模式， 打破杀虫剂抗性，和ii）利用中肠营养转运蛋白，以促进膳食吸收的亲， 杀虫剂该项目将为蚊子生物学和杀虫剂领域提供重大进展 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.