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Drug development against Entamoeba histolytica

抗溶组织阿米巴药物开发

基本信息

批准号：
9978458
负责人：
UPINDER SINGH
金额：
$ 23.66万
依托单位：
STANFORD UNIVERSITY
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：
2020-03-10 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978458
关键词：
Address Adverse drug effect Algorithms Amoeba genus Anaerobic Bacteria Animal Model Basic Science Biology Bioterrorism Cause of Death Cells Cessation of life Characteristics Clinical Clinical Data Clinical Research Clinical Trials Colitis Collaborations Cyst Data Developing Countries Development Disease Drug Delivery Systems Drug Kinetics Drug Screening Drug Targeting Dysentery Entamoeba Entamoeba histolytica Excision Exploratory/Developmental Grant FDA approved Food Contamination Foundations Funding Future Goals Grant HepG2 Human Institutes Invaded Kinetics Lactation Lead Letters Libraries Life Cycle Stages Liver Abscess Medical Methods Metronidazole Metronidazole resistance Morbidity - disease rate National Institute of Allergy and Infectious Disease Nitroimidazoles Organism Orphan Outcome Parasite resistance Parasites Pathogenesis Pathogenicity Pharmaceutical Preparations Pharmacotherapy Phase Recording of previous events Recrudescences Regimen Research Resistance Safety Scientist Series Speed Testing Therapeutic Time Tissues Toxic effect Translations Treatment Protocols Woman Work base comparative efficacy contaminated water cost data access design diarrheal disease drug development drug discovery experience high throughput screening human pathogen improved in vivo in vivo evaluation mortality mouse model neglect new therapeutic target novel novel therapeutics pathogen pregnant screening standard of care success transmission process

项目摘要

ABSTRACT Entamoeba histolytica causes dysentery and liver abscesses with invasive disease in 50 million people annually. Despite being an important human pathogen, this organism is poorly studied, has very limited therapeutic options, and has no significant drug development pipeline. Thus, there is a critical need for new drugs against this pathogenic ameba. We chose a compound screening approach using the ReFRAME library, which was generated by Calibr and the Bill and Melinda Gates Foundation to have high-value hits with the vast majority of compounds having been tested in humans. We have completed screening of ~11,000 compounds against E. histolytica and identified 156 primary (~1.3%) hits. We subsequently performed confirmatory testing and confirmed 50 hits with EC50 £15µM. By considering FDA approval status, clinical trial data, hepG2 cell toxicity and potency against E. histolytica trophozoites, we identified 19 high-priority compounds for further testing in this grant cycle. Of these 19 priority compounds, 9 have been FDA approved or have FDA orphan designation and an additional 7 have been in late stage human clinical trials (Phase II or III); 14 have improved efficacy compared to metronidazole. Thus, these 19 compounds are great options for a repurposing approach. In this R21 grant, we will characterize these high value hits in the following two aims. In Aim 1, we will test these compounds against Entamoeba cysts (encysting cells and mature cysts), metronidazole resistant Entamoeba, and clinical isolates. We will also determine the kinetics of parasite killing with each compound and the delay of parasite recrudescence after drug removal. Based on these results and analysis of pharmacokinetic data on the compounds, in Aim 2, we will select ~2-5 select compounds to test in vivo efficacy in a mouse model of Entamoeba colitis. Successful completion of this work will identify ~2 lead compounds/series with activity against Entamoeba histolytica. Based on our experience with amebae, significant drug development expertise at Stanford and UCSD, and a cadre of outstanding collaborators, we are confident of a successful outcome.

摘要溶组织内阿米巴导致5000万人感染痢疾和肝脓肿每年。尽管是一种重要的人类病原体，但这种生物的研究很少，治疗选择，并且没有重要的药物开发管道。因此，迫切需要新的对抗这种致病性阿米巴的药物我们选择了使用ReFRAME库的化合物筛选方法，这是由Calibr和比尔和梅林达盖茨基金会产生的，大多数化合物已在人体中进行了测试。我们已经完成了约11，000种化合物的筛选针对大肠histolytica，并确定了156个主要命中（~1.3%）。我们随后进行了确认性测试并确认了50个命中，EC 50为15µM。通过考虑FDA批准状态，临床试验数据，hepG 2细胞对大肠杆菌的毒力和效价。我们鉴定了19种高优先级化合物，在这个周期里测试。在这19种优先化合物中，9种已获得FDA批准或具有FDA孤儿药另有7个已进入晚期人体临床试验（II期或III期）; 14个已改善与甲硝哒唑相比。因此，这19种化合物是再利用方法的绝佳选择。在这个R21补助金，我们将在以下两个目标中描述这些高价值的命中。在目标1中，我们将测试这些化合物抗内阿米巴包囊（包囊细胞和成熟包囊），甲硝唑耐药内阿米巴和临床分离株。我们还将确定每种化合物杀死寄生虫的动力学以及药物去除后寄生虫复发的延迟。根据这些结果和分析，在目标2中，我们将选择约2-5种选定化合物进行体内测试内阿米巴结肠炎小鼠模型中的有效性。成功完成这项工作将确定约2个潜在客户具有抗溶组织内阿米巴活性的化合物/系列。根据我们的经验，在斯坦福大学和加州大学圣地亚哥分校的重要药物开发专业知识，以及优秀的合作者骨干，我们有信心取得成功。