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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

基本信息

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
项目类别：
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

项目摘要

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.

土壤传播蠕虫或土壤传播线虫（STN）感染是肠道寄生虫