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

描述（由申请方提供）：微小隐孢子虫是一种AIDS-OI病原体和B类病原体，可导致人类和动物严重水样腹泻。这种寄生虫可在免疫功能低下的个体中引起长期的、威胁生命的感染，并且是AIDS患者中相当程度的发病率和死亡率的原因。也因为感染性卵囊对化学应激具有高度的抵抗力，C。水是一种重要的水， 和食源性病原体，是NIH生物防御计划中的B类病原体之一。目前，没有药物被FDA批准用于治疗免疫功能低下患者的隐孢子虫病，尽管在美国有一种单一的药物（硝唑尼特）被批准用于免疫功能正常的患者。因此，迫切需要开发新的抗隐孢子虫药物，特别是针对艾滋病患者的新型药物。鼓励最近的发展“现有药物的再利用”潜在的新的适应症，以及基于我们的意想不到的观察，标记的药物可以强烈抑制隐孢子虫在体外的生长，我们计划通过筛选所有现有的药物，其潜在的抗隐孢子虫活性在体外和体内扩展我们的发现。简言之，我们将利用已建立的模型和测定来实现以下两个目标：目标1。使用我们完善开发和改进的qRT-PCR试验，在体外从已知药物中鉴定潜在的抗隐孢子虫化合物。目标二。使用隐孢子虫感染的急性和慢性小鼠模型确定选定药物的体内抗隐孢子虫功效。大多数被筛选的化合物是目前或以前上市的药物。所提出的实验检查药物对寄生虫生长的直接影响，在体外和体内。因此，如果在任何FDA批准的药物中观察到令人满意的体外和体内抗隐孢子虫活性，这些有效的药物可以迅速进入临床试验，并重新用于成为治疗人类隐孢子虫感染的新药，从而加速抗隐孢子虫药物的发现和开发。此外，该项目还将产生大量数据，概述几乎所有现有和废弃药物的活动。这些宝贵的数据可用于分析抗隐孢子虫的构效关系（SAR），以指导未来的药物开发。

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.