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

土传蠕虫或土传线虫(STN)感染是肠道寄生虫 线虫，主要是蛔虫、钩虫和鞭虫。它们是最流行的寄生虫之一 并在儿童中造成严重的发病率，包括发育迟缓、智力和教育 损伤、营养不良、贫血和较低的未来收入；它们也对 孕妇和工人的生产力。单剂量大剂量给药治疗sTNS 依赖于单一的药物类别苯并咪唑(BZS)。BZS对鞭虫和鞭虫的疗效较差 对钩虫的药效变化很大。已在sTNS中检测到BZ抗性等位基因，并有 对所有寄生虫的低BZ疗效的明显例子。新的作用机制和广泛的效力 STNS的治疗迫在眉睫。然而，使用STN的高通量筛选(HTS)平台 到目前为止，寄生虫还没有被开发出来，这将极大地促进药物发现。在这里，一个新的 描述和验证了使用两种高度分散的STN寄生虫的STN药物发现的流水线，以及 新的HTS平台，在管道开始时合并(Z系数0.53)。整体而言 这项应用的目的是通过应用来识别可以广泛靶向STN寄生虫的安全化合物 这个新的HTS平台和管道。两个包含21,153个高质量和良好特性的文库 化合物将被筛选出来。此HTS中的活动(预计约1800个)将通过筛选进行下选 抗钩虫成虫和鞭毛虫成虫 成虫，这两种寄生虫都与人类STN药物发现高度相关。具有二元性的化合物 数据挖掘/化学信息学将进一步优先考虑对这些不同寄生虫的活性， 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 对抗这两个物种的成虫。来自这些研究的前10-20种活性物质将在啮齿动物身上进行测试 对真正的寄生虫感染具有体内驱虫功效。在这些研究之后，在体内 药代动力学(PK)研究，重点文库和结构-活性-关系研究，以及初步 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，为未来的应用。在成功执行这项拟议的研究计划后， 我们预计已经确定了1-4种新的、广谱的抗STN化合物(驱虫剂)，为未来做好准备 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.