Development of vector-specific, resistance-breaking insecticides to reduce malari

开发病媒特异性、突破耐药性的杀虫剂以减少疟疾

• 批准号: 8237040
• 负责人: Paul R Carlier
• 金额: $ 66.12万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237040
• 关键词: Acetylcholinesterase; Acetylcholinesterase Inhibitors; Acute; Address; Africa South of the Sahara; African; Agriculture; Amines; Anopheles Genus; Anopheles gambiae; Antidotes; Binding; Binding Sites; Biological Assay; Carbamates; Carboxylic Ester Hydrolases; Catalytic Domain; Child; Cholinesterase Inhibitors; Computer Simulation; Crystallization; Culicidae; Decision Trees; Development; Disease Vectors; Drug Metabolic Detoxication; Enzymes; Fostering; Funding; Goals; Human; Insecticide Resistance; Insecticides; Intervention; Length; Life; Ligands; Malaria; Measures; Mediating; Metabolic; Mus; Mutation; Oral; Paper; Performance; Peripheral; Permethrin; Persons; Phenylcarbamates; Probability; Propoxur; Relative (related person); Research; Research Design; Research Methodology; Resistance; Risk; Roentgen Rays; Route; Safety; Screening procedure; Site; Stream; Structural Biologist; Structure; Testing; TimeLine; Toxic effect; Translating; Translational Research; United States National Institutes of Health; Variant; base; carboxylesterase; chemical synthesis; design; disease transmission; improved; in vitro Assay; inhibitor/antagonist; innovation; killings; mutant; novel; pharmacophore; pyrethroid; research study; resilience; resistance mechanism; resistant strain; success; transmission process; vector; vector control; vector mosquito; virtual

DESCRIPTION (provided by applicant): Malaria exacts a terrible toll in sub-Saharan Africa, killing an estimated 1-2 million persons each year, mostly children. Pyrethroid-based insecticide treated nets (pyrethroid ITNs) provide the first line of defense against disease transmission, but emerging resistant strains of the disease vector (Anopheles gambiae) threaten to render these ITNs ineffective. Our broad objective is to develop a new class of acetylcholinesterase (AChE)-targeting insecticide for deployment on ITNs, that is safe for use, effective against current pyrethroid- and AChE- resistant strains, and is less likely to foster emergence of new AChE-resistant strains. Thus our goal is consistent with the focus of the solicitation on novel interventions for the control of Malaria. FNIH-sponsored research from 2005-2008 enabled us to make significant progress towards our long-term goal. Further support from NIH will allow us to establish proof of concept that our novel AChE-based insecticide, deployed on an ITN, would constitute a superior intervention to manage the disease vector. Thus our goal is also consistent with the stated aim of the solicitation to fund translational research. To achieve our goal we have assembled a team of chemists, structural biologists, entomologists, and toxicologists. Our specific aims are to 1)improve stability of An. gambiae AChE (AgAChE)-selective carbamates to oxidative detoxification; 2)acquire 3D structural information on AgAChE to optimize inhibition potency and selectivity; 3)develop bivalent carbamates for resilience to target-site mutation; 4)identify strategies to mitigate against carboxylesterase-mediated detoxification; and 5)make a preliminary assessment of mammalian toxicity of the most promising insecticides to emerge from these studies. To guide us through the proposed five years of research we have prepared a detailed timeline and decision tree that incorporate five integrated streams of insecticide discovery for optimizing field performance and human safety. Moreover the built-in complementarity of the chemical synthesis routes and the optimization approaches (e.g. resilience to both target-site and metabolic resistance mechanisms) means that unexpected difficulty in one stream need not slow progress in the other streams. These multiple approaches increase the probability of project success. Malaria exacts a terrible toll in sub-Saharan African, and at present the first line of defense against the mosquito vector of the disease is provided by insecticide treated nets (ITNs). However, growing resistance to the class of insecticide used on the nets threatens to make this protection ineffective. We propose to develop a new class of insecticide that is safe for ITN deployment, effective against current insecticide-resistant mosquitoes, and less likely to promote emergence of new resistant strains.

描述（由申请人提供）：疟疾在撒哈拉以南非洲造成的巨大损失，每年造成1-200万人丧生，其中大多数是儿童。基于拟除虫菊酯的杀虫剂处理的网（拟除虫菊酯ITN）提供了针对疾病传播的第一道防线，但是疾病载体的新兴抗性菌株（Anopheles Gambiae）威胁着使这些ITN无效。我们的广泛目标是开发一种新的乙酰胆碱酯酶（ACHE）靶向ITN部署的促杀虫剂，可安全使用，有效地抵抗当前的拟甲虫素和耐药菌菌株，并且不太可能促进新的ACHE耐药性的出现。因此，我们的目标与征集对疟疾控制的新干预措施的重点一致。 FNIH赞助的2005 - 2008年研究使我们能够朝着长期目标取得重大进展。 NIH的进一步支持将使我们能够建立概念证明，即我们的新型基于ACHE的杀虫剂部署在ITN上，将构成管理疾病载体的卓越干预措施。因此，我们的目标也与邀请资助转化研究的既定目标一致。 为了实现我们的目标，我们组建了一个化学家，结构生物学家，昆虫学家和毒理学家团队。我们的具体目的是1）提高AN的稳定性。冈比亚ACHE（Agache） - 选择性氨基甲酸盐氧化解毒； 2）获取有关Agache的3D结构信息，以优化抑制效力和选择性； 3）开发二价氨基甲酸酯，以使目标位点突变具有弹性； 4）确定减轻羧酸酯酶介导的排毒的策略； 5）对这些研究最有前途的杀虫剂的哺乳动物毒性进行初步评估。为了指导我们进行拟议的五年研究，我们准备了一个详细的时间表和决策树，该时间表结合了五个集成的杀虫剂发现流，以优化现场性能和人类安全。此外，化学合成途径的内置互补性和优化方法（例如，对目标位点和代谢抗性机制的韧性）意味着，一个流中的意外困难不需要在其他流中降低进度。这些多种方法增加了项目成功的可能性。 疟疾在撒哈拉以南非洲造成了可怕的损失，目前，针对该疾病的蚊子载体的第一道防线是由杀虫剂处理的网（ITN）提供的。但是，对网络上使用的杀虫剂类别的耐药性越来越有可能使这种保护无效。我们建议开发一种新型的杀虫剂，该杀虫剂可安全，可对当前耐杀虫剂的蚊子有效，并且不太可能促进新的抗性菌株出现。