Discovery of GPCR-targeted insecticides for malaria mosquito control

发现用于控制疟疾蚊子的 GPCR 靶向杀虫剂

• 批准号: 9435634
• 负责人: Yoonseong Park
• 金额: $ 24.06万
• 依托单位: KANSAS 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: 2017-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9435634
• 关键词: Agonist; Anopheles gambiae; Area; Arthropods; Beds; Behavior; Behavioral; Binding; Biological; Biological Assay; Biology; Biotechnology; C-terminal; Cessation of life; Characteristics; Chemicals; Chinese Hamster Ovary Cell; Collection; Communicable Diseases; Computer software; Culicidae; Dengue; Dependence; Developing Countries; Development; Discipline; Diuresis; Effectiveness; Endocrine; Evolution; Fluorescence; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic; Hormone Receptor; Hormones; Infection; Insecta; Insecticide Resistance; Insecticides; Juvenile Hormones; Laboratories; Libraries; Ligands; Malaria; Mammals; Mediating; Metabolic; Methods; Molting; Mosquito Control; Mosquito-borne infectious disease; NMR Spectroscopy; Names; Neurons; Neurotoxins; Outcome; Pattern; Peptide Signal Sequences; Peptides; Pesticides; Pharmacology; Population; Prevention; Process; Property; RNA Interference; Regulation; Reporter; Reporting; Research Infrastructure; Research Personnel; Role; Signal Transduction; Sodium Channel; Specificity; Structure; Techniques; Technology; Testing; Ticks; Time; Universities; Vector-transmitted infectious disease; Yellow Fever; base; chemical property; cheminformatics; computational chemistry; feeding; genetic evolution; genetic resistance; high throughput screening; human disease; improved; mosquitocidal; neurotoxic; novel; novel strategies; pathogen; peptide structure; pyrethroid; receptor; release of sequestered calcium ion into cytoplasm; repository; screening; transmission process; vector; vector mosquito; zika fever

Project Summary/Abstract Numerous species of mosquitoes are vectors of many pathogens that cause devastating infectious diseases, such as malaria, Dengue, yellow fever, and Zika fever. More than 1 million deaths and up to 700 million cases of infections by mosquito-borne vector diseases (nearly 10% of the total world population) are reported each year. The use of chemical insecticides has been a highly efficient method for the disruption of the pathogen transmission cycle by suppressing the vector population, whereas the evolution of insecticide resistance has hampered the efficacy of currently available classes of insecticides. We propose to establish a new approach for the development of a novel class of mosquitocidal compounds. In the era of new biotechnology, the search for small bioactive compounds using high throughput screening (HTS) is now a robust and accessible technology that can offer substantive dividends for users. The target molecule for the HTS assay we propose is a G protein-coupled receptor (GPCR), named ecdysis-triggering hormone receptor (ETH-R), which is a receptor for a crucial hormone in the unique biology of arthropods for shedding of their external cuticle during molting and for regulation of another crucial endocrine factor juvenile hormone in mosquito. The ETH-R is an ideal target that will allow for the identification of an effective product with significantly improved selectivity toward mammals and even different orders of insects, which will permit the suppression of the mosquito population without significant environmental damage. Target-based discovery of insecticidal compounds will provide a novel example of a biorational approach for the development of pesticide. In this proposal, we aim to identify compounds that act on ETH receptor of the most devastating malaria mosquito (Anopheles gambiae, AgETH-R) by using HTS. We will also identify the structure of the peptide ligands ETH to understand the chemical interaction of the ligand on the binding pocket of the ETH-R. Four investigators in two different Universities will collaborate for the Specific Aims that require diverse areas of disciplines. The specific aims are: 1) High throughput screening for identifying agonists and antagonists acting on AgETH-R [Drs. Roy and Park], 2) Nuclear magnetic resonance (NMR) spectroscopy to determine the structures of AgETH and similar peptide ligands [Drs. Prakash and Park], and 3) Cheminformatics to identify the chemical signature of the hits and the chemical clusters for further tests [Drs. Huan and Park].

项目总结/摘要 许多种类的蚊子是许多病原体的载体，这些病原体导致毁灭性的传染病， 如疟疾、登革热、黄热病和寨卡热。超过100万例死亡和高达7亿例病例 据报告，每年有2000万人（占世界总人口的近10%）感染蚊媒疾病， 年使用化学杀虫剂是破坏病原体的高效方法 通过抑制病媒种群来减少传播周期，而杀虫剂抗药性的演变 这阻碍了现有杀虫剂种类的效力。我们建议建立一个新的方法 用于开发一类新的杀蚊化合物。在新生物技术时代， 对于小的生物活性化合物，使用高通量筛选（HTS）现在是一个强大的和可访问的 可以为用户带来实质性红利的技术。我们提出的HTS测定的靶分子是 G蛋白偶联受体（GPCR），命名为蜕皮触发激素受体（ETH-R），是一种 在节肢动物独特的生物学中，一种关键激素的受体，用于在生长过程中脱落外角质层 蜕皮和调节蚊子体内另一个重要的内分泌因子保幼激素。ETH-R是一种 理想的目标，将允许识别具有显著提高的选择性的有效产品 对哺乳动物，甚至不同的昆虫目，这将允许抑制蚊子 没有严重的环境破坏。基于目标的杀虫化合物发现将 为农药的开发提供了一个新的生物合理方法的例子。在本建议中，我们的目标是 鉴定作用于最具破坏性的疟疾蚊子（冈比亚按蚊， AgETH-R）。我们还将确定肽配体ETH的结构，以了解其在体内的作用。 ETH-R结合口袋上配体的化学相互作用。四个调查员在两个不同的 大学将为需要不同学科领域的特定目标进行合作。具体目标 1）用于鉴定作用于AgETH-R的激动剂和拮抗剂的高通量筛选[Drs. Roy和 2）核磁共振（NMR）光谱，以确定AgETH和类似物的结构 肽配体[Prakash和Park博士]，和3）化学信息学，以鉴定命中物的化学特征 和化学簇进行进一步的测试[Huan博士和Park博士]。