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

自动化高通量化合物筛选广泛活性的抗寄生虫线虫药物

• 批准号: 10089408
• 负责人: RAFFI V AROIAN
• 金额: $ 65.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089408
• 关键词: Adult; Alleles; Ancylostoma (genus); Ancylostoma caninum; Anemia; Animals; Anthelmintics; Antiparasitic Agents; Ascaris; Ascaris lumbricoides; Automation; Biological Assay; Caenorhabditis elegans; Cell Line; Chemicals; Child; Clinic; Clinical Research; Colon Carcinoma; Communities; Developing Countries; Development; Diagnosis; Disease; Dose; Drug Kinetics; Economics; Evaluation; Failure; Follow-Up Studies; Future; Growth; Hamsters; Health; Helminths; Hookworms; Human; Impaired cognition; Impairment; In Vitro; Individual; Intestines; Larva; Lead; Libraries; Malignant Epithelial Cell; Malnutrition; Mammalian Cell; Maternal complication; Methods; Morbidity - disease rate; Mothers; Multi-Drug Resistance; Mus; Necator; Nematoda; Nematode infections; Parasite resistance; Parasites; Parasitic infection; Parasitic nematode; Pharmaceutical Preparations; Phylogenetic Analysis; Planet Earth; Poverty; Preclinical Drug Development; Pregnancy Complications; Pregnant Women; Primary carcinoma of the liver cells; Process; Production; Productivity; Recipe; Research; Resistance; Rodent; Soil; Structure-Activity Relationship; System; Testing; Therapeutic; Toxic effect; Trichocephalus trichiura; Trichuris; Validation; analog; base; benzimidazole; benzimidazole resistance; cheminformatics; data mining; drug candidate; drug discovery; egg; enteric infection; high throughput screening; in silico; in vitro testing; in vivo; in vivo evaluation; indexing; infected vector rodent; molecular modeling; novel; pre-clinical; preclinical study; productivity loss; resistance allele; response; scaffold; screening

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.

土壤传播的蠕虫或土壤传播线虫（STN）感染是肠道寄生虫 线虫，主要是阿斯卡里斯，钩虫和鞭子。它们是最普遍的寄生虫之一 在地球上并引起儿童的严重发病率，包括增长，智力和教育 损害，营养不良，贫血和较低的未来收入；他们也对 孕妇和工人的生产力。单剂量药物管理（MDA）治疗STN 依靠单个药物类别，即苯甲酰唑（BZS）。 BZ对鞭虫和 针对钩虫的高度可变功效。在STN中检测到BZ抗性等位基因，并且有 对所有寄生虫的BZ功效的明确例子。新的行动机制和广泛有效的 迫切需要使用STN的疗法。但是，使用STN的高通量筛选（HTS）平台 迄今为止尚未开发寄生虫，这将极大地促进药物发现。在这里，一个新 使用两个高度不同的STN寄生虫进行STN药物发现的管道被描述和验证，也是如此 新的HTS平台在管道开头（z因子0.53）。总体 本应用的目的是识别可以通过申请来广泛针对STN寄生虫的安全化合物 这款新的HTS平台和管道。两个高质量且特征良好的图书馆，包含21,153 化合物将被筛选。该HTS的活性人士（约1800个预测）将通过筛选下降。 针对成年ceylanicum钩虫成人寄生虫和trichuris muris鞭子虫 成年寄生虫，两者都与人类STN药物发现高度相关。双重化合物 数据挖掘/化学信息学将进一步优先考虑这些发散寄生虫的活动， 哺乳动物细胞毒性研究，耐BZ的钩虫测定以及体外剂量反应研究 反对两种物种的成年寄生虫。这些研究的前10-20名活跃物将在啮齿动物中测试 用于对真正的寄生虫感染的体内驱虫功效。遵循这些研究，体内 药代动力学（PK）研究，集中文库和结构活动关系研究以及初始 作用机理（MOA）研究将进行。这项研究将为更多 未来应用的详细后续研究。成功执行该拟议的研究计划后 我们希望已经确定了1-4个新的，广泛活跃的抗STN化合物（Anthelmintics） 临床前和临床研究。