Evaluation of marketed drugs for rapid development as anti-cryptosporidal agents

评价上市药物作为抗隐孢子虫药物的快速开发

基本信息

批准号：
8528014
负责人：
GUAN ZHU
金额：
$ 18.61万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528014
关键词：
2,4-thiazolidinedione Acquired Immunodeficiency Syndrome Acute Acyl Coenzyme A Animals Anti-HIV Agents Ants Biological Assay Categories Cessation of life Chemicals Chlorine Chronic Cities Clinical Trials Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Data Development Diarrhea Disease Outbreaks Drug Design Evaluation FDA approved Future Growth Human Immunocompetent Immunocompromised Host In Vitro Individual Infection Life Ligase Marketing Modeling Morbidity - disease rate Oocysts Parasites Patients Pharmaceutical Preparations Resistance Stress Structure-Activity Relationship Thiazolidinediones United States United States National Institutes of Health Water Water Supply Wisconsin base biodefense drug development drug discovery drug market foodborne pathogen gastrointestinal epithelium improved in vitro activity in vivo inhibitor/antagonist mortality mouse model nitazoxanide novel pathogen programs research study screening

项目摘要

DESCRIPTION (provided by applicant): Cryptosporidium parvum is an AIDS-OI pathogen and Category B agent that can cause severe watery diarrhea in humans and animals. This parasite can cause prolonged, life threatening infection in immunocompromised individuals, and is responsible for a substantial degree of morbidity and mortality in AIDS patients. Also because the infectious oocysts are highly resistant to chemical stresses, C. parvum is a significant water- and food-borne pathogen and one of the category B agent in the NIH biodefense program. Currently, no drug is FDA-approved to treat cryptosporidiosis in immunocompromised patients, although a single drug (nitazoxanide) is approved for use in immunocompetent patients in the United States. Therefore, there is an urgent need to develop new anti-Cryptosporidium drugs, particularly new drugs for AIDS patients. Encouraged by the recent development in "repurposing of existing drugs" for potential new indications, as well as based on our unexpected observations that a marked drug could strongly inhibit the growth of Cryptosporidium in vitro, we plan to extend our discovery by screening all existing drugs for their potential ant-cryptosporidia activities in vitro and in vivo. Briefly, we will take advantage of established models and assays t achieve the following two aims: Aim 1. To identify potential anti-cryptosporidial compounds from known drugs in vitro using our well- developed and improved qRT-PCR assay. Aim 2. To determine anti-cryptosporidial efficacy of select drugs in vivo using acute and chronic mouse models of cryptosporidial infection. The majority of the compounds being screened are currently or previously marketed drugs. The proposed experiments examine the direct effects of drugs on the parasite growth in vitro and in vivo. Therefore, if satisfactory anti-cryptosporidial activitie in vitro and in vivo are observed among any of the FDS-approved drugs, these effective drugs can be rapidly moved to clinical trials and repurposed to become new drugs to treat cryptosporidial infection in humans, thus accelerating the drug discovery and development against Cryptosporidium. Furthermore, the project will nonetheless produce a large amount of data that profiles the activities of nearly all existing and abandoned drugs. The invaluable data can be used to analyze the structure-activity relationship (SAR) against Cryptosporidium to guide future drug development.

描述（由申请人提供）：隐孢子虫Parvum是一种艾滋病病原体和B类药物，可引起人类和动物的严重水性腹泻。这种寄生虫可能会导致免疫功能低下的个体延长生命的感染，并导致艾滋病患者的大量发病率和死亡率。同样，由于传染性卵囊对化学应激高度抗性，因此，孢子虫是一种重要的水。 NIH Biodefense计划中的食物传播病原体和B类药物之一。目前，尽管批准了一种用于免疫功能低下的患者的药物治疗免疫功能低下患者的隐孢子虫病的药物，但在美国批准了一种用于免疫能力的患者。因此，迫切需要开发新的抗氯孢子虫药物，尤其是针对艾滋病患者的新药。在最近在“现有药物重新利用现有药物”方面的发展的鼓励下，我们的意外观察结果是，明显的药物可以在体外强烈抑制隐孢子虫的增长，我们计划通过筛选所有现有药物来扩展我们的发现，以筛选所有现有药物，以实现其潜在的Ant-cryptosporidia在体外和Intivo中的潜在抗合性孢子虫活性。简而言之，我们将利用既定的两个目的来利用既定模型，并实现以下两个目标：使用我们的良好开发和改进的QRT-PCR分析，从已知药物中识别出潜在的抗晶体孢子型化合物。 AIM 2。使用隐孢子虫感染的急性和慢性小鼠模型，确定体内精选药物的抗孢子孢子效应。正在筛选的大多数化合物目前是或以前销售的药物。提出的实验检查了药物对体外和体内寄生虫生长的直接影响。因此，如果在任何经过FDS批准的药物中观察到令人满意的抗晶体孢子型活动，则可以在任何一个经过FDS批准的药物中观察到这些有效的药物，可以迅速转移到临床试验中，并重新利用成为治疗人类隐孢子虫感染的新药物，从而使药物发现和发育抗体抗菌。此外，该项目仍将产生大量数据，以介绍几乎所有现有药物的活动。宝贵的数据可用于分析针对隐孢子虫的结构活性关系（SAR），以指导未来的药物开发。