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了可怕的死亡人数，估计每年造成 1-200 万人死亡，其中大部分是儿童。以拟除虫菊酯为基础的杀虫剂处理过的蚊帐（拟除虫菊酯ITN）提供了抵御疾病传播的第一道防线，但新出现的病媒（冈比亚按蚊）耐药菌株可能使这些ITN失效。我们的总体目标是开发一种新型乙酰胆碱酯酶 (AChE) 靶向杀虫剂，用于在杀虫剂蚊帐 (ITN) 上部署，该杀虫剂使用安全，可有效对抗目前的拟除虫菊酯和乙酰胆碱酯酶抗性菌株，并且不太可能促进新的乙酰胆碱酯酶 (AChE) 的出现。耐药菌株。因此，我们的目标与控制疟疾的新型干预措施征集的重点是一致的。 2005 年至 2008 年 FNIH 资助的研究使我们在实现长期目标方面取得了重大进展。 NIH 的进一步支持将使我们能够建立概念证明，证明我们部署在 ITN 上的新型基于乙酰胆碱酯酶的杀虫剂将构成管理疾病媒介的卓越干预措施。因此，我们的目标也与资助转化研究的既定目标一致。 为了实现我们的目标，我们组建了一支由化学家、结构生物学家、昆虫学家和毒理学家组成的团队。我们的具体目标是 1）提高 An 的稳定性。冈比亚乙酰胆碱酯酶（AgAChE）-选择性氨基甲酸酯进行氧化解毒； 2）获取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增强对靶位点突变的抵抗力； 4）确定减轻羧酸酯酶介导的解毒作用的策略； 5）对这些研究中出现的最有前途的杀虫剂的哺乳动物毒性进行初步评估。为了指导我们完成拟议的五年研究，我们准备了详细的时间表和决策树，其中包含杀虫剂发现的五个综合流，以优化现场性能和人类安全。此外，化学合成路线和优化方法的内在互补性（例如对靶位点和代谢抗性机制的恢复力）意味着一个流中的意外困难不会减慢其他流的进展。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地区造成了严重的伤亡，目前针对该疾病蚊媒的第一道防线是经过杀虫剂处理的蚊帐 (ITN)。然而，人们对蚊帐上使用的杀虫剂类别的抵抗力不断增强，有可能使这种保护失效。我们建议开发一类新型杀虫剂，该杀虫剂对于ITN部署是安全的，对当前对杀虫剂具有抗药性的蚊子有效，并且不太可能促进新的抗药菌株的出现。