Automated high throughput compound screening for broadly active anti-parasitic nematode drugs

土传蠕虫或土传线虫感染是肠道寄生虫病 线虫，主要是蛔虫、钩虫和鞭虫。它们是最常见的寄生虫之一 造成儿童严重发病，包括生长发育迟缓、智力和教育发育不良， 残疾、营养不良、贫血和未来收入降低;它们也对 孕妇和工人的生产力。单剂量大剂量给药（MDA）治疗STNs 依赖于单一的药物类别，苯并咪唑（BZ）。BZ对鞭虫的疗效差， 对钩虫的效力差异很大。BZ抗性等位基因已在STNs中检测到， BZ对所有寄生虫的低效力的明确例子。新的作用机制和广泛的效力 因此，迫切需要对STN进行治疗。然而，使用PCR的高通量筛选（HTS）平台， 迄今为止还没有开发出寄生虫，这将极大地促进药物发现。在这里，一个新的 描述并验证了使用两种高度不同的寄生虫进行药物发现的管道， 新HTS平台，在管道开始时纳入（Z因子0.53）。整体 本申请的目的是通过施用本发明的化合物来鉴定可广泛靶向寄生虫的安全化合物。 这个新的HTS平台和管道两个高质量和特色鲜明的图书馆，共21，153个 将筛选化合物。来自该HTS的活性物质（约1800个预测值）将通过筛选进行下选 针对锡兰钩口线虫成虫寄生虫和针对小鼠鞭虫 成虫寄生虫，这两者都与人类药物发现高度相关。二元化合物 通过数据挖掘/化学信息学将对这些不同寄生虫的活性进一步优先化， 哺乳动物细胞毒性研究、抗BZ钩虫试验以及体外剂量反应研究 两种寄生虫的成虫。这些研究中的前10 - 20种活性物质将在啮齿动物中进行测试 用于对抗真正的寄生虫感染的体内驱虫功效。在这些研究之后，在体内 药代动力学（PK）研究、聚焦文库和结构-活性-关系研究，以及初始 将开展行动机制（MoA）研究。这项研究将为更多的 详细的后续研究，以备将来应用。在成功执行了这项拟议的研究计划后， 我们希望已经鉴定出1 - 4种新的、广泛活性的抗蠕虫化合物（驱虫剂），为将来做好准备 临床前和临床研究。

Soil-transmitted helminth or soil-transmitted nematode (STN) infections are intestinal parasitic nematodes, mainly Ascaris, hookworms, and whipworms. They are amongst the most prevalent parasites on earth and cause severe morbidity in children, including growth stunting, intellectual and educational impairment, malnutrition, anemia, and lower future earning; they also have significant impacts on pregnant women and worker productivity. Single dose mass drug administration (MDA) to treat STNs relies on a single drug class, the benzimidazoles (BZs). BZs have poor efficacy against whipworms and highly variable efficacy against hookworms. BZ resistance alleles have been detected in STNs and there are clear examples of low BZ efficacy against all parasites. New mechanism-of-action and broadly potent therapies for STNs are urgently needed. However, high throughput screening (HTS) platforms using STN parasites have not been developed to date, which would greatly facilitate drug discovery. Here, a new pipeline for STN drug discovery using two highly divergent STN parasites is described and validated, as is a new HTS platform that is incorporated at the beginning of the pipeline (Z factor 0.53). The overall objective of this application is to identify safe compounds that can broadly target STN parasites by applying this new HTS platform and pipeline. Two high-quality and well-characterized libraries containing 21,153 compounds will be screened. Actives (~1800 predicted) from this HTS will be down-selected by screening against adult Ancylostoma ceylanicum hookworm adult parasites and against Trichuris muris whipworm adult parasites, both which are highly relevant for human STN drug discovery. Compounds that are dually active against these divergent parasites will be further prioritized by data mining/chemoinformatics, mammalian cell toxicity studies, BZ-resistant hookworm assays, as well as in vitro dose-response studies against adult parasites from both species. The top 10-20 actives from these studies will be tested in rodents for in vivo deworming efficacy against genuine parasitic infections. Following these studies, in vivo pharmacokinetic (PK) studies, focused library and Structure-Activity-Relationship studies, and initial mechanism of action (MoA) studies will be carried out. This research will lay the groundwork for more detailed follow up studies for future applications. After successful execution of this proposed research plan, we expect to have identified 1-4 new, broadly active anti-STN compounds (anthelmintics) primed for future pre-clinical and clinical studies.