Novel Macrofilaricidal Compounds: Target Identification and Chemical Optimizatio

描述(申请人提供)：寄生虫感染了超过1.4亿人，在80个国家中有多达10亿人面临风险。淋巴丝虫病在受影响地区造成巨大的健康和经济负担，是导致长期残疾的第二大原因。2000年，包括世界卫生组织(WHO)在内的国际组织发起了一项倡议，通过每年大规模给药来消除淋巴丝虫病。尽管用于这一雄心勃勃的计划的化合物(伊维菌素、阿苯达唑、二乙基乙胺嘧啶)对杀死幼虫(微丝虫)有效，但寄生虫(大丝虫)的成虫宿主仍能存活并可在人类宿主中停留十年。此外，大规模治疗造成的极端选择压力也伴随着最近的寄生虫抗药性证据。使用伊维菌素减少盘尾丝虫病的运动也面临着类似的挑战。这项SBIR建议的长期目标是开发急需的大杀丝虫化合物，以消除成虫寄生虫库，并保护现有药物免受广泛耐药性的发展。 发散最近实施了一项专利技术，这代表了分子建模的根本进步，并允许识别具有共同作用模式的结构无关的化合物。分歧已经成功地用这种方法创建了一个有价值的化学集合，对动植物寄生线虫具有很高的有效命中率(~17%)。该系列中的一些化合物在体外对雌、雄马来丝虫也具有非常有前景的大丝虫杀灭活性。在第一阶段将实现两个目标。第一，由于我们的化合物代表了一种广泛和新颖的杀线虫作用模式，DISPISTION将启动线虫的遗传研究，以确定化合物的分子靶标。第二，将通过获取和合成类似物来推行结构活性和优化策略。合成的分子将在体外对成虫进行评估，然后在哺乳动物细胞系中进行细胞毒性和微粒体稳定性的测试。在第二阶段的研究中，有希望的分子将在啮齿动物模型中进行丝虫病控制的评估，以及毒理学和药代动力学评估。在第一阶段基因筛选中确定的分子靶标将被克隆和鉴定，用于开发下一代导联，并最终用于临床使用的项目化合物的耐药性监测。这项工作的预期结果是鉴定有效的铅分子，以一种新的作用模式展示在体内的大丝状杀菌活性。与表现出致力于全球卫生公平的机构(如盖茨基金会和世卫组织)合作，第三阶段的工作将侧重于启动人类临床试验，最终目标是大幅减少丝虫病对人类健康的负担。 项目简介：寄生线虫(蛔虫)目前感染全球超过10亿人，造成严重的发病率和经济负担。该项目的目标是确定和开发抗击丝虫的迫切需要的药物，丝虫会导致一些最致命的人类传染病--象皮病和河盲症。

DESCRIPTION (provided by applicant): Parasitic infect over 140 million people, with up to one billion at risk in 80 countries. Lymphatic filariasis creates an enormous health and economic burden within affected areas and is the second leading cause of long-term disability. In 2000, international groups including the World Health Organization (WHO) launched an initiative to eliminate lymphatic filariasis by annual mass drug administration. Although the compounds available for this ambitious program (ivermectin, albendazole, diethylcarbamazine) are effective at killing larvae (microfilariae), the adult reservoir of parasites (macrofilariae) survive and can remain in the human host for a decade. In addition, the extreme selective pressure caused by mass treatment has been accompanied by recent evidence of parasite drug resistance. Similar challenges face the campaigns to reduce onchocerciasis with ivermectin. The long- term objective of this SBIR proposal is to develop desperately needed macrofilaricidal compounds that can eliminate the adult parasite reservoir and protect current drugs from the development of broad resistance. Divergence has recently implemented a proprietary technology that represents a fundamental advance in molecular modeling and allows the identification of structurally unrelated compounds that have a shared mode of action. Divergence has already succeeded with this approach in creating a valuable chemical collection with a high rate (~17%) of potent hits against animal and plant parasitic nematodes. A number of compounds in the collection also have very promising macrofilaricidal activity against female and male Brugia malayi filarial worms in vitro. Two objectives will be accomplished during Phase I. First, as our compounds represent a broad and novel nematicidal mode of action, Divergence will initiate genetic studies in C. elegans to identify the compounds' molecular target. Second, structure-activity and optimization strategies will be pursued through the acquisition and synthesis of analogs. The resultant molecules will be evaluated against adult B. malayi in vitro and subsequently assayed for cytotoxicity in a mammalian cell line and microsomal stability. During Phase II studies, promising molecules will progress to evaluation of filarial control in a rodent model along with toxicology and pharmacokinetic evaluation. Molecular targets identified in the Phase I genetic screen will be cloned and characterized for use in development of next generation leads and eventual resistance monitoring in a project compound reaching clinical use. The expected outcome of this work is the identification of potent lead molecules that demonstrate in vivo macrofilaricidal activity with a novel mode of action. In collaboration with agencies that have demonstrated a commitment to global health equity (such as the Gates Foundation and WHO), Phase III efforts will focus on the initiation of clinical trials in humans with the ultimate goal of greatly reducing the human health burden of filarial diseases. Project Narrative: Parasitic nematodes (roundworms) currently infect over one billion people globally, causing severe morbidity and economic burden. The goal of this project to identify and develop desperately needed drugs to combat filarial nematodes, which cause some of the most pernicious infectious diseases in humans - elephantiasis and river blindness.