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

描述（由申请人提供）：小隐孢子虫是一种AIDS-OI病原体和B类病原体，可引起人类和动物严重的水样腹泻。这种寄生虫可在免疫功能低下的个体中引起长期的、危及生命的感染，并在很大程度上导致艾滋病患者的发病率和死亡率。此外，由于感染性卵囊对化学胁迫具有很强的抵抗力，小孢子虫是一种重要的水-

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. PUBLIC HEALTH RELEVANCE: Project Narrative Cryptosporidium parvum is a Category B agent and an opportunistic pathogen in AIDS patients. Its infection in AIDS patients can be prolonged and deadly, for which no treatment is yet available. This is largely due to the technical difficulties in manipulating this parasite in laboratory and to the unusual metabolic features that are still poorly understood. This project takes advantage of an improved drug testing assay to unbiasedly, directly screen all existing drugs on their efficacies on the parasite growth in vitro. Top positive drugs will be further tested in vivo in a mouse model of chronic cryptosporidiosis. The majority of tested compounds are marked drugs for which toxicity and pharmacokinetics are known. Therefore, if any effective drugs are identified in this study, they can be quickly moved into clinic trials and/or "repurposed" as new drugs to treat cryptosporidiosis in humans and/or animals.