New mode-of-action chemistries for mosquito control

控制蚊子的新化学作用模式

• 批准号: 9198750
• 负责人: CATHERINE A HILL
• 金额: $ 23.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198750
• 关键词: Adult; Adverse effects; Aedes; Affinity; Agonist; Allosteric Site; Arthropods; Binding; Biological Assay; Cells; Cellular Assay; Chemistry; Communicable Diseases; Consensus; Coupling; Culicidae; Cyclic AMP; Dengue; Development; Disease; Disease Vectors; Dopamine; Dopamine Antagonists; Dopamine Receptor; Drug Receptors; Environment; Flupenthixol; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Goals; Health; Human; In Vitro; Insect Vectors; Insecticide Resistance; Insecticides; Intervention; Larva; Lead; Ligands; MAP Kinase Gene; MAPK3 gene; Measures; Mediating; Medicine; Molecular Conformation; Mosquito Control; Organism; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Population; Positioning Attribute; Property; Radiolabeled; Receptor Activation; Research; Safety; Series; Signal Pathway; Signal Transduction; Site; Specificity; Stimulus; Structure; Technology; Testing; Work; Yellow Fever; base; biosecurity; disorder control; high throughput screening; improved; in vitro Assay; inhibitor/antagonist; innovation; mortality; neurotoxic; next generation; novel; public health relevance; receptor; receptor binding; response; screening; small molecule; therapy outcome; transcriptome; vector; vector control; vector mosquito

 DESCRIPTION (provided by applicant): Transformative solutions are required to control and eliminate diseases transmitted by mosquitoes and protect human health and biosecurity. Mosquito control relies heavily on insecticides that are neurotoxic to many organisms, including humans, and ineffective against insecticide-resistant mosquitoes. The long-term goal of our research is the development of new, safer interventions to control mosquito vectors. We lead a mature research effort to develop a new class of insecticides that target G protein-coupled receptors (GPCRs) in mosquitoes. Our chemistries are selective for mosquito dopamine receptors (DARs) and operate via modes that are different to existing products. This work is significant because new mode-of-action insecticides would provide continued yet safer mosquito and disease control. Our goal on this two-year developmental project is to advance novel, complementary "allosteric modulator" technology to enhance the safety profile and insecticidal properties of GPCR-directed insecticides. Small molecule allosteric modulators are widely used in human medicine to improve the specificity of GPCR acting drugs and minimize adverse side-effects. Allosteric drugs can stimulate or inhibit receptor activity. These chemistries offer selectivity through binding at unique sites on the receptor and/or by causing the receptor to engage a specific cell-signaling pathway (signaling bias). Allosteric modulators of GPCRs can be detected using in vitro pharmacological assays. On this project, we will explore the potential of allosteric modulator technology at the DAR AaDOP2 from the Aedes aegypti mosquito vector of dengue and yellow fever. Our project goal is to identify and evaluate the pharmacology of mosquito DAR modulators. This objective will be accomplished via work under two Specific Aims: Specific Aim 1: Discover inhibitors that modulate activity at AaDOP2. Allosteric modulation of receptor activity can present as changes to the potency, efficacy and affinity of a chemistries at the receptor. We will develop cellular assays to identify negative allosteric modulators (NAMs) that reduce the potency, efficacy and affinity of chemistries at AaDOP2. Specific Aim 2: Discover negative allosteric modulators that selectively inhibit AaDOP2 signaling pathways. Modulation can present as the biased engagement of a receptor-mediated cell signaling pathway. Cellular assays that measure common signaling endpoints will be used to screen for biased NAMs and explore the phenomenon of signaling bias at AaDOP2. At the successful completion of the proposed exploratory studies, we will have identified and assessed the pharmacological properties of one or more NAMs active at the Ae. aegypti DAR. This will enable expanded efforts to develop unique small molecule technologies against multiple mosquito vectors of disease.

 描述（由申请人提供）：需要变革性的解决方案来控制和消除蚊子传播的疾病，保护人类健康和生物安全。蚊虫控制严重依赖杀虫剂，这些杀虫剂对包括人类在内的许多生物体具有神经毒性，对抗药性蚊子无效。我们研究的长期目标是开发新的，更安全的干预措施来控制蚊子媒介。我们领导了一项成熟的研究工作，以开发一种针对蚊子G蛋白偶联受体（GPCR）的新型杀虫剂。我们的化学品对蚊子多巴胺受体（DAR）具有选择性，并通过与现有产品不同的模式进行操作。这项工作意义重大，因为新的作用模式杀虫剂将提供持续但更安全的蚊子和疾病控制。我们在这个为期两年的开发项目中的目标是推进新的、互补的“变构调节剂”技术，以提高GPCR导向杀虫剂的安全性和杀虫特性。小分子变构调节剂广泛用于人类医学中以提高GPCR作用药物的特异性并使不良副作用最小化。变构药物可以刺激或抑制受体活性。这些化学物质通过结合在受体上的独特位点和/或通过使受体参与特定的细胞信号传导途径（信号传导偏好）来提供选择性。GPCR的变构调节剂可以使用体外药理学测定来检测。在这个项目中，我们将探索在DAR AaDOP 2从埃及伊蚊登革热和黄热病的蚊子载体变构调节剂技术的潜力。我们的项目目标是鉴定和评估蚊子DAR调节剂的药理学。这一目标将通过两个具体目标下的工作来实现：具体目标1：发现调节AaDOP 2活性的抑制剂。受体活性的变构调节可以表现为化学物质对受体的效力、功效和亲和力的变化。我们将开发细胞测定以鉴定负变构调节剂（NAM），所述负变构调节剂降低AaDOP 2处的化学物质的效力、功效和亲和力。具体目标2：发现选择性抑制AaDOP 2信号通路的负变构调节剂。调节可以表现为受体介导的细胞信号传导途径的偏置接合。测量共同信号传导终点的细胞测定将用于筛选偏倚的NAM，并探索AaDOP 2的信号传导偏倚现象。在成功完成拟定的探索性研究后，我们将确定并评估一种或多种在Ae有活性的NAM的药理学特性。埃及这将使扩大努力，以开发独特的小分子技术，对付多种蚊子疾病载体。