Preclinical optimization of a parasiticidal drug for cryptosporidiosis

隐孢子虫病杀寄生虫药物的临床前优化

• 批准号: 9882947
• 负责人: David Griggs
• 金额: $ 62.03万
• 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: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9882947
• 关键词: ADME Study; Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Animals; Arrhythmia; Biliary; Biochemical; Biological Assay; Biology; Blood; CRISPR/Cas technology; Cardiotoxicity; Characteristics; Child; Chronic; Clinical; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Cytochrome P450; Diarrhea; Disease Outbreaks; Dissection; Dose; Drug Design; Drug Interactions; Drug Targeting; Drug resistance; Enzymes; Ethers; Europe; Excretory function; Exposure to; Future; Genes; Genetic; Gnotobiotic; Goals; Human; Immunocompromised Host; In Vitro; Infant; Infection; Intestines; Lead; Life; Malaria; Methods; Modeling; Molecular Mechanisms of Action; Molecular Target; Mus; Mutation; Oral; Outcome; Parasites; Patients; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Piperazines; Placebos; Plasmodium; Potassium Channel; Property; Proteins; Public Health; Research; Resistance; Resources; Safety; Series; Small Intestines; Staphylococcus hominis; Structure; Testing; Tissues; Toxic effect; Toxicology; Transplant Recipients; United States; Validation; Work; analog; base; chemical synthesis; chemoproteomics; clinical candidate; clinical development; clinical efficacy; cost; diarrheal disease; drug candidate; drug development; drug discovery; enteric infection; genome sequencing; improved; in vitro Assay; in vivo; intestinal epithelium; lead optimization; mouse model; nitazoxanide; novel; patient population; pharmacokinetics and pharmacodynamics; pre-clinical; programs; resistant Plasmodium falciparum; screening; success; waterborne; whole genome

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 or 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 long-term goal of this research program is to develop improved drugs to treat cryptosporidiosis. In this project, a parasiticidal piperazine- based lead compound with extraordinary in vivo efficacy that was identified by phenotypic screening will be optimized, and its molecular mechanism of action will be determined. The lead optimization program is guided by an ideal target product profile and milestones to provide a pre-clinical lead that is likely to be effective in all patient populations affected by Cryptosporidium and has safety characteristics suitable for treatment of infants, minimal drug-drug interactions, minimal oral dosing requirements, stability in the tropics, and a low manufacturing cost. The methods for lead optimization bring together novel in vitro assays and a highly immunocompromised mouse model of cryptosporidiosis with well-established pharmacology and medicinal chemistry approaches. For this, cyclic rounds of chemical synthesis will be combined with in vitro Cryptosporidium assays, in vitro ADME studies, mouse PK studies, and a chronic mouse model of C. parvum infection. A piglet model will then be used to test clinical efficacy against C. hominis. The method for drug target identification will take advantage of the lead compound's activity against related malaria parasites to identify mutations associated with drug resistance and candidate drug targets, followed by CRISPR/Cas9 validation of mutations in C. parvum and biochemical methods to assess direct protein-drug interactions. Success would yield an optimized clinical candidate that is ready to be advanced to testing in regulatory toxicology studies, and a validated drug target that will accelerate drug development by enabling target-based drug design and target-based screening efforts to identify additional chemotypes. Given the dire need for new cryptosporidiosis drugs, the public health impact of success could be extremely significant.

项目总结 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，原因 艾滋病患者和移植患者中无法治愈的腹泻，是水媒腹泻的最常见原因 美国爆发疫情。几乎所有的人类隐孢子虫病病例都是由于感染了 肠上皮与隐孢子虫的两种寄生虫之一，微小隐孢子虫或人隐孢子虫。 硝唑尼特是唯一被批准的药物，在其他健康的成年人中是有效的，但不幸的是， 在儿童中的疗效(~56%)，相当于艾滋病患者的安慰剂。这项研究的长期目标是 该计划是开发治疗隐孢子虫病的改良药物。在这个项目中，一种杀寄生虫的哌嗪- 通过表型筛选确定的具有非凡体内疗效的基础先导化合物将是 优化后，将确定其作用的分子机理。引导者优化程序被引导 通过理想的目标产品简介和里程碑来提供可能对所有人都有效的临床前领先 受隐孢子虫影响的患者群体，具有适合婴儿治疗的安全特征， 最小的药物相互作用，最低的口服剂量要求，热带地区的稳定性，以及低 制造成本。前线优化的方法结合了新的体外分析方法和高度 免疫低下小鼠隐孢子虫病模型的药理和药物研究 化学接近了。为此，循环循环的化学合成将与体外合成相结合 隐孢子虫检测、体外ADME研究、小鼠PK研究和微小隐孢子虫慢性小鼠模型 感染。然后将使用仔猪模型来测试对抗人毛滴虫的临床效果。一种用药的方法 目标识别将利用先导化合物对相关疟疾寄生虫的活性来 确定与耐药相关的突变和候选药物靶点，然后是CRISPR/Cas9 微小隐孢子虫突变的验证和评估蛋白质-药物直接相互作用的生化方法。 成功将产生一种优化的临床候选方案，准备在监管部门进行测试 毒理学研究，以及有效的药物靶点，通过实现基于目标的药物开发来加速药物开发 药物设计和基于目标的筛选工作，以确定更多的化学类型。鉴于对新技术的迫切需求 隐孢子虫病药物的成功对公众健康的影响可能是极其显著的。