Repurposing the EMD-Serono "mini-library" for Cryptosporidium drug development

重新利用 EMD-Serono“迷你库”进行隐孢子虫药物开发

基本信息

批准号：
10320256
负责人：
CHRISTOPHER D HUSTON
金额：
$ 45.48万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320256
关键词：
1-Phosphatidylinositol 3-Kinase ADME Study Acquired Immunodeficiency Syndrome Address Adult Affect Animals Biological Assay Biology Cells Characteristics Chemicals Child Chronic Clinical Research Collaborations Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Cytochrome P450 Data Development Diarrhea Disease Outbreaks Drug Interactions Drug Kinetics Europe Follow-Up Studies German population Goals Growth Growth Inhibitors Human Immunocompromised Host In Vitro Industry Industry Collaboration Infant Infection Intestinal Absorption Investments Knowledge Laboratories Lead Libraries Life Malaria Malnutrition Methods Microscopy Modeling Mus Parasites Patients Periodicity Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Placebos Property Public Health Research Risk Safety Screening Result Series Small Intestines Solubility Specific qualifier value Staphylococcus hominis Structure-Activity Relationship Testing Toxicology Transplant Recipients United States Work analog base chemical synthesis chronic infection clinical candidate cytotoxicity diarrheal disease drug development drug discovery efficacy study efficacy testing experience follow-up improved in vitro Assay in vivo inhibitor/antagonist interest intestinal epithelium kinase inhibitor lead optimization lead series microbial mouse model nitazoxanide novel novel therapeutics patient population phosphodiesterase V success waterborne willingness

项目摘要

PROJECT SUMMARY Cryptosporidiosis is amongst the most important causes of life-threatening diarrhea in children globally, causes incurable diarrhea in AIDS and transplant patients, and is the most common cause of waterborne diarrheal outbreaks in the United States. Almost all human cases of cryptosporidiosis are due to infection of the small intestinal epithelium with one of two species of Cryptosporidium parasites, C. parvum and C. hominis. Nitazoxanide, the only approved drug, is efficacious in otherwise healthy adults, but unfortunately, has limited efficacy (~56%) in children and is equivalent to a placebo in AIDS patients. The goal of this project is to address the need for new anti-Cryptosporidium drugs via an exciting collaboration between the German pharmaceutical company EMD-Serono, an academic Cryptosporidium biologist, an academic medicinal chemist with extensive prior industry experience, and an academic biologist (also with extensive industry experience) whose laboratory specializes in in vitro and in vivo drug pharmacology. The developmental cascade to accomplish this is guided by an ideal target product profile for a drug effective in all affected patient populations; the methods bring together novel in vitro assays and a highly immunocompromised mouse model of cryptosporidiosis with well-established pharmacology and medicinal chemistry approaches. The R21 phase will deliver two lead compounds with anti- Cryptosporidium efficacy in a chronic mouse model of infection, along with knowledge of key compound characteristics and potential safety concerns. The open access EMD-Serono “mini-library” has already been screened and three promising Cryptosporidium growth inhibitors were identified that are suitable for follow-up. A second EMD-Serono mini-library will be screened to identify additional potential starting points. Validated Cryptosporidium growth inhibitors will then be prioritized using 1) assays to assess if compounds are cidal or static, selective, and active against C. hominis, and 2) existing EMD-Serono pharmacokinetic and safety data and available EMD-Serono analogs for structure-activity relationship (SAR) studies. After prioritization and testing available analogs in vitro, mouse pharmacokinetic studies and efficacy studies will be performed. If the progression milestones are met, the R33 phase will result in optimization of one lead chemical series for potency and safety. The other series will be held in backup. For this, cyclic rounds of chemical synthesis will be combined with in vitro Cryptosporidium assays, in vitro ADME studies, mouse PK studies, and the chronic mouse model of cryptosporidiosis. Success would yield an optimized clinical candidate that is ready to be advanced to testing in large animal diarrhea models and regulatory toxicology studies. Given the dire need for new cryptosporidiosis drugs, the public health impact of success could be extremely significant.

项目概要隐孢子虫病是全球儿童危及生命的腹泻的最重要原因之一，艾滋病和移植患者无法治愈的腹泻，是水源性腹泻的最常见原因在美国，几乎所有隐孢子虫病的人类病例都是由小型隐孢子虫感染引起的。肠上皮上有两种隐孢子虫寄生虫（小隐孢子虫和人隐孢子虫）之一。硝唑尼特是唯一被批准的药物，对其他方面健康的成年人有效，但不幸的是，其疗效有限对儿童的疗效（约 56%），相当于艾滋病患者的安慰剂。该项目的目标是解决这一问题。德国制药公司之间令人兴奋的合作满足了对新型抗隐孢子虫药物的需求 EMD-Serono 公司，一位学术隐孢子虫生物学家，一位学术药物化学家，拥有广泛的研究经验先前的行业经验，以及其实验室的学术生物学家（也具有丰富的行业经验）专门研究体外和体内药物药理学，指导实现这一目标的发展级联。这些方法汇集了所有受影响患者群体的药物疗效的理想目标产品概况；新颖的体外测定和高度免疫功能低下的隐孢子虫病小鼠模型 R21相将提供两种具有抗-药物作用的先导化合物。隐孢子虫在慢性感染小鼠模型中的功效以及关键化合物的知识开放获取的 EMD-Serono“迷你图书馆”已经存在。筛选并确定了三种有前景的隐孢子虫生长抑制剂，适合后续研究。将筛选第二个 EMD-Serono 迷你库，以确定其他潜在的已验证起点。然后，将使用 1) 测定法对隐孢子虫生长抑制剂进行优先排序，以评估化合物是否具有杀灭性或杀灭性。静态、选择性和活性对抗人念珠菌，以及 2) 现有的 EMD-Serono 药代动力学和安全性数据以及可用于结构-活性关系 (SAR) 研究的 EMD-Serono 类似物。如果可以的话，将进行体外测试可用的类似物、小鼠药代动力学研究和功效研究。达到里程碑后，R33 进展阶段将优化一个先导化学系列的效力为此，将结合化学合成的循环轮次。体外隐孢子虫检测、体外 ADME 研究、小鼠 PK 研究以及慢性小鼠模型成功将产生一个优化的临床候选药物，准备好进行测试。鉴于迫切需要新的隐孢子虫病，大型动物腹泻模型和监管毒理学研究。药物的成功对公众健康的影响可能极其重大。