Novel Macrofilaricidal Compounds: Target Identification and Chemical Optimizatio

描述（由申请人提供）：寄生虫感染超过1.4亿人，在80个国家中有多达10亿人处于危险之中。淋巴丝虫病在受影响地区造成巨大的健康和经济负担，是造成长期残疾的第二大原因。2000年，包括世界卫生组织（世卫组织）在内的国际组织发起了一项倡议，通过每年大规模药物管理来消除淋巴丝虫病。尽管可用于这一雄心勃勃的计划的化合物（伊维菌素、阿苯达唑、乙胺嗪）在杀死幼虫（微丝蚴）方面是有效的，但寄生虫（微丝蚴）的成虫宿主存活下来，并可以在人类宿主中保留十年。此外，大规模治疗造成的极端选择压力伴随着寄生虫抗药性的最新证据。用伊维菌素减少盘尾丝虫病的运动也面临类似的挑战。该SBIR提案的长期目标是开发迫切需要的杀微丝蚴化合物，其可以消除成虫寄生虫储库并保护当前药物免受广泛耐药性的发展。 Divergence最近实施了一项专有技术，该技术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化合物。Divergence已经成功地使用这种方法创建了一个有价值的化学品收集，对动物和植物寄生线虫具有高比率（约17%）的有效命中率。该系列中的许多化合物在体外对雌性和雄性马来丝虫也具有非常有希望的杀大型丝虫活性。第一阶段将实现两个目标。首先，由于我们的化合物代表了一种广泛而新颖的杀线虫作用模式，Divergence将启动C. elegans来确定化合物的分子靶点。第二，结构活性和优化策略将通过类似物的获取和合成来实现。将针对成人B评价所得分子。Malayi体外培养，随后测定哺乳动物细胞系中的细胞毒性和微粒体稳定性。在II期研究期间，有希望的分子将在啮齿动物模型中评估丝虫控制沿着毒理学和药代动力学评估。在I期遗传筛选中鉴定的分子靶标将被克隆和表征，用于开发下一代先导化合物，并最终监测达到临床用途的项目化合物的耐药性。这项工作的预期成果是确定有效的铅分子，证明在体内的巨丝虫活性与一种新的行动模式。第三阶段的工作将与已表明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，重点是启动人体临床试验，最终目标是大大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迫切需要的药物来对抗丝虫线虫，这会导致人类一些最致命的传染病-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.