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

• 批准号: 10548847
• 负责人: CHRISTOPHER D HUSTON
• 金额: $ 44.74万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 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/10548847
• 关键词: 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; Medicine; Methods; Microscopy; Modeling; Mus; PIK3CG gene; 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; Structure-Activity Relationship; Testing; Toxicology; Transplant Recipients; United States; Work; analog; 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; interest; intestinal epithelium; kinase inhibitor; lead optimization; lead series; meter; microbial; mouse model; nitazoxanide; novel; novel therapeutics; patient population; phosphodiesterase V; success; waterborne; willingness

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 隐孢子虫病是全球威胁儿童生命的腹泻的最重要原因之一， 艾滋病和器官移植患者的不治之症，也是水传播性腹泻最常见的原因 在美国爆发。几乎所有的人类隐孢子虫病病例都是由于感染了 肠上皮内寄生两种隐孢子虫之一，C. parvum和C.人类 硝唑尼特是唯一被批准的药物，对其他健康的成年人有效，但不幸的是， 在儿童中的有效性（~56%），在艾滋病患者中与安慰剂相当。该项目的目标是解决 通过德国制药公司和德国制药公司之间令人兴奋的合作， 公司EMD-Serono，学术隐孢子虫生物学家，学术药物化学家，广泛的 之前的行业经验，以及一位学术生物学家（也具有丰富的行业经验），其实验室 专攻体外和体内药物药理学。实现这一目标的发展级联是指导 通过对所有受影响患者群体有效的药物的理想目标产品概况;该方法汇集了 新的体外试验和高度免疫受损的隐孢子虫病小鼠模型， 药理学和药物化学方法。R21阶段将提供两种具有抗- 隐孢子虫在慢性小鼠感染模型中的疗效，沿着关键化合物的知识 特征和潜在的安全问题。开放获取的EMD-Serono“迷你图书馆”已经 筛选和三个有前途的隐孢子虫生长抑制剂进行了鉴定，适合于后续。 将筛选第二个EMD-Serono小型文库，以确定其他潜在的起点。验证 然后将使用1）测定来优先考虑隐孢子虫生长抑制剂，以评估化合物是否是杀灭性的或 对C.人，和2）现有的EMD-Serono药代动力学和安全性数据 和可用于结构-活性关系（SAR）研究的EMD-Serono类似物。在确定优先次序和 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。如果 如果达到进展里程碑，R33阶段将优化一个先导化学品系列的效价 和安全性其他系列将作为备份。为此，化学合成的循环回合将结合 通过体外隐孢子虫试验、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人，准备进行测试， 大型动物腹泻模型和监管毒理学研究。鉴于对新型隐孢子虫病的迫切需求 药物，成功的公共卫生影响可能是极其重要的。