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损失，每年造成大约1- 200万人死亡，其中大多数是儿童。基于拟除虫菊酯的杀虫剂处理过的蚊帐（拟除虫菊酯蚊帐）提供了防止疾病传播的第一道防线，但是新出现的病媒（冈比亚按蚊）耐药菌株有可能使这些蚊帐失效。我们的主要目标是开发一类新的乙酰胆碱酯酶（AChE）靶向杀虫剂，用于ITNs部署，该杀虫剂使用安全，对现有的拟除虫菊酯和AChE耐药菌株有效，并且不太可能促进新的AChE耐药菌株的出现。因此，我们的目标与本次征集活动对控制疟疾的新干预措施的重点是一致的。从2005年到2008年，fnih赞助的研究使我们在实现长期目标方面取得了重大进展。美国国立卫生研究院的进一步支持将使我们能够建立概念证明，我们的新型基于乙酰氨基酚的杀虫剂，部署在ITN上，将构成管理病媒的优越干预措施。因此，我们的目标也与邀请资助转化研究的既定目标一致。