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.

项目摘要隐孢子虫病是全球儿童威胁生命的腹泻的最重要原因之一艾滋病和移植患者的腹泻，是水性腹泻的最常见原因美国爆发。几乎所有人类隐孢子虫病病例都是由于小小的感染肠上皮，有两种隐孢子虫寄生虫之一，C。parvum和C. hominis。 Nitazoxanide是唯一的批准药物，在其他健康成年人中有效，但不幸的是，儿童的效率（约56％），相当于艾滋病患者的安慰剂。该项目的目的是解决需要通过德国药品之间的激动人心的合作来建立新的抗晶型孢子虫药物公司Emd-Serono，一名学术隐孢子虫生物学家，一名学术药物学家，广泛先前的行业经验，以及一位学术生物学家（也具有丰富的行业经验），其实验室专门从事体外和体内药理学。实现这一目标的发展级联是指导的通过理想的目标产品概况，用于在所有受影响的患者人群中有效的药物；这些方法汇集在一起新颖的体外测定和高度免疫功能低下的小鼠隐孢子虫病模型药理学和医学化学方法。 R21相将提供两种抗抗化合物慢性小鼠感染模型中的隐孢子虫效率以及关键化合物的知识特征和潜在的安全问题。 Open Access Emd-Serono“迷你图书馆”已经是鉴定出适合随访的筛选和三个有希望的隐孢子虫生长抑制剂。将筛选第二个EMD-Serono Mini-Library，以识别其他潜在的起点。经过验证然后，使用1）测定法对隐孢子虫生长抑制剂进行优先级，以评估化合物是CIDAL还是静态，选择性和对抗hominis的静态和活跃，2）现有的EMD-Serono药代动力学和安全数据以及用于结构活性关系（SAR）研究的可用EMD-Serono类似物。优先级后将在体外测试可用的类似物，小鼠药代动力学研究和效率研究。如果是达到了进程里程碑，R33相将导致优化一个铅化学系列的效力和安全。另一个系列将在备用中举行。为此，将组合化学合成的循环弹通过体外隐孢子虫测定，体外ADME研究，小鼠PK研究和慢性小鼠模型隐孢子虫病。成功将产生一个优化的临床候选者，该候选者准备进行测试大型动物腹泻模型和调节毒理学研究。考虑到需要新的隐孢子虫病毒品，成功的公共卫生影响可能非常重要。