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: 10328540
• 负责人: RAFFI V AROIAN
• 金额: $ 37.44万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328540
• 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; Persons; 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.

土源性蠕虫或土源性线虫 (STN) 感染属于肠道寄生虫 线虫，主要是蛔虫、钩虫和鞭虫。它们是最常见的寄生虫之一 地球上并导致儿童严重发病，包括生长发育迟缓、智力和教育障碍 损伤、营养不良、贫血和未来收入较低；它们也对 孕妇和工人的生产力。单剂量大规模给药 (MDA) 治疗 STN 依赖单一药物类别，即苯并咪唑 (BZ)。 BZs 对鞭虫的功效较差， 对钩虫的功效差异很大。 STN 中已检测到 BZ 抗性等位基因，并且存在 BZ 对所有寄生虫的功效较低的明显例子。新的作用机制和广泛的效力 迫切需要针对 STN 的治疗。然而，使用 STN 的高通量筛选 (HTS) 平台 迄今为止，寄生虫尚未被开发出来，这将极大地促进药物发现。在这里，一个新的 描述并验证了使用两种高度不同的 STN 寄生虫进行 STN 药物发现的管道，就像 新的 HTS 平台被纳入管道的开头（Z 因子 0.53）。整体 本申请的目的是通过应用来识别可广泛针对 STN 寄生虫的安全化合物 这个新的高温超导平台和管道。两个高质量且特征明确的库，包含 21,153 个 将筛选化合物。该 HTS 中的活性物质（预计约 1800 个）将通过筛选被向下选择 对抗成虫锡兰钩虫成虫寄生虫和对抗鼠鞭虫 成虫寄生虫，两者都与人类 STN 药物发现高度相关。具有双重性质的化合物 数据挖掘/化学信息学将进一步优先考虑积极对抗这些不同的寄生虫， 哺乳动物细胞毒性研究、BZ 抗性钩虫测定以及体外剂量反应研究 对抗这两个物种的成虫寄生虫。这些研究中排名前 10-20 的活性成分将在啮齿类动物中进行测试 针对真正的寄生虫感染的体内驱虫功效。根据这些研究，在体内 药代动力学 (PK) 研究、重点库和结构-活性-关系研究以及初步 将进行作用机制（MoA）研究。这项研究将为更多的研究奠定基础 为未来的应用进行详细的后续研究。在成功执行本提议的研究计划后， 我们预计将鉴定出 1-4 种新的、具有广泛活性的抗 STN 化合物（驱虫药），为未来做好准备 临床前和临床研究。