Developing botanical-derived chemical tools for controlling mosquito vectors

开发植物源化学工具来控制蚊媒

• 批准号: 10596724
• 负责人: Xiaolin Cheng
• 金额: $ 64.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596724
• 关键词: 3-Dimensional; ANK1 gene; Adult; Aedes; Agonist; Anopheles gambiae; Arboviruses; Benchmarking; Binding; Biological Assay; Blood; Botanicals; Cell membrane; Centers for Disease Control and Prevention (U.S.); Chemicals; Culex (Genus); Culicidae; Custom; Dengue; Dengue Fever; Development; Disease; Docking; Electrophysiology (science); Exhibits; Family; Female; Goals; Grant; Human; Insecticide Resistance; Insecticides; Knowledge; Lead; Libraries; Machine Learning; Madagascar; Malaria; Medical; Medicinal Plants; Modeling; Molecular; Mosquito Control; Mosquito-borne infectious disease; Muscle; Natural Products; Paralysed; Pharmaceutical Chemistry; Plants; Process; Quantitative Structure-Activity Relationship; Research; Resistance; Sesquiterpenes; Specificity; Structural Models; Structure; TRPA channel; Time; Toxic Actions; United States Environmental Protection Agency; Visceral; Yellow Fever; ZIKA; Zika Virus; base; chikungunya; covalent bond; cytotoxicity; design; human disease; improved; in silico; in vivo Bioassay; insight; iterative design; next generation; novel; prevent; pyrethroid; screening; small molecule libraries; structural biology; tool; transmission process; vector; vector mosquito; virtual; virtual library

Project Summary: The yellow fever mosquito Aedes aegypti is the principal vector of several medically-important arboviruses that have recently emerged or re-emerged globally, such as chikungunya, dengue, and Zika. The mitigation of mosquito-borne diseases often relies on preventing mosquitoes from biting humans via the use of chemical control tools, such as insecticides and/or repellents. However, the emergence of insecticide resistance in mosquitoes has reduced the efficacy of the most widely used control agents (e.g., pyrethroids), resulting in a need to develop insecticides with novel modes of action. Moreover, only a few mosquito repellents are currently registered by the Environmental Protection Agency and recommended by the Centers for Disease Control. Limited knowledge on the modes of action of these repellents has hampered development and optimization of biorational mosquito repellents. Thus, chemical control tools with novel modes of action are needed to improve the management of mosquito vectors. With the support of an R21 grant, we discovered a drimane sesquiterpene (cinnamodial, CDIAL) from the bark of an endemic medicinal plant of Madagascar (Cinnamosma fragrans; family Canellaceae) that kills larval and adult female Ae. aegypti. The mode of toxic action of CDIAL in mosquitoes involves paralysis of visceral muscle associated with activation of Ca2+ channels, a unique mode of action compared to pyrethroids. Moreover, we found that CDIAL is a potent agonist of mosquito transient receptor potential ankyrin 1 (TRPA1) channels, an established mode of action for some mosquito repellents and antifeedants. The goal of the proposed R01 research is to develop novel CDIAL-based chemical tools for controlling mosquitoes with Ae. aegypti as our primary study species. In Aim 1, we will use natural products, medicinal chemistry, in vivo bioassays, and machine learning to develop quantitative structure-activity relationship (QSAR) models of the insecticidal and visceral muscle paralysis activities of CDIAL. These models will inform the iterative design of CDIAL derivatives that are at least 100-fold more potent than CDIAL as insecticides. In Aim 2, we will use in silico modeling and heterologous expression approaches to determine how CDIAL respectively binds to mosquito and human TRPA1 channels. This knowledge will inform the design and iterative QSAR-based optimization of CDIAL-based agonists that are at least 100-times more specific for mosquito over human TRPA1 channels and repel adult female mosquitoes. In addition, the in silico structural models of mosquito TRPA1 will be used to virtually screen a natural product library of over 400,000 compounds to discover novel mosquito-selective TRPA1 agonists that repel mosquitoes. Lead compounds from both Aims will be considered ‘candidates’ if they meet mammalian cytotoxicity benchmarks and are efficacious against multiple mosquito vectors (Anopheles gambiae, Culex quinquefasciatus). Collectively, results from both aims will facilitate development of next-generation chemical tools to control mosquito vectors.

项目概要： 黄热病蚊子埃及伊蚊是几种具有重要医学意义的虫媒病毒的主要媒介， 最近在全球范围内出现或重新出现的疾病，例如基孔肯雅热、登革热和寨卡病毒。 蚊媒疾病通常依赖于使用化学物质来防止蚊子叮咬人类 防治工具，例如杀虫剂和/或驱虫剂。然而，杀虫剂抗药性的出现。 蚊子降低了最广泛使用的控制剂（例如拟除虫菊酯）的功效，导致 需要开发具有新颖作用方式的杀虫剂，此外，只有少数驱蚊剂。 目前已由环境保护局注册并由疾病中心推荐 对这些驱虫剂作用方式的了解有限，阻碍了开发和利用。 因此，具有新颖作用方式的化学防治工具正在被优化。 在 R21 拨款的支持下，我们发现了一个需要改善蚊媒管理的问题。 来自马达加斯加特有药用植物树皮的倍半萜（肉桂醛，CDIAL） （Cinnamosma fragrans；Canellaceae 科）可杀死埃及伊蚊的幼虫和成年雌性。 CDIAL 在蚊子中的作用涉及与 Ca2+ 激活相关的内脏肌肉麻痹 与拟除虫菊酯相比，CDIAL 是一种独特的作用方式。 蚊子瞬时受体电位锚蛋白 1 (TRPA1) 通道的激动剂，这是一种既定的作用模式 一些驱蚊剂和拒食剂 拟议的 R01 研究的目标是开发新型药物。 基于 CDIAL 的化学工具，用于控制以埃及伊蚊为主要研究物种的蚊子。 1、我们将利用天然产物、药物化学、体内生物测定和机器学习来开发 杀虫和内脏肌麻痹的定量构效关系（QSAR）模型 这些模型将为至少 100 倍的 CDIAL 衍生品的迭代设计提供信息。 比 CDIAL 更有效的杀虫剂 在目标 2 中，我们将在计算机建模和异源表达中使用。 确定 CDIAL 如何分别与蚊子和人类 TRPA1 通道结合的方法。 知识将为基于 CDIAL 的激动剂的设计和基于 QSAR 的迭代优化提供信息，这些激动剂 对蚊子的特异性比人类 TRPA1 通道高至少 100 倍，并且可以驱除成年雌性蚊子。 此外，蚊子 TRPA1 的计算机结构模型将用于虚拟筛选天然产品 包含超过 400,000 种化合物的文库，用于发现可驱除蚊子的新型选择性 TRPA1 激动剂 如果来自这两个目标的铅化合物遇到哺乳动物，则它们将被视为“候选者”。 细胞毒性基准，对多种蚊媒（冈比亚按蚊、库蚊）有效 总的来说，这两个目标的结果将促进下一代化学品的开发。 控制蚊媒的工具。