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

基本信息

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
项目类别：
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

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 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美国爆发疫情。几乎所有人类隐孢子虫病病例都是由小隐孢子虫感染引起的。肠上皮上有两种隐孢子虫寄生虫（小隐孢子虫或人隐孢子虫）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。本研究的长期目标计划是开发改进的药物来治疗隐孢子虫病。在这个项目中，一种杀寄生虫哌嗪- 通过表型筛选鉴定出的具有非凡体内功效的先导化合物将被优化，并确定其分子作用机制。引导先导化合物优化计划通过理想的目标产品概况和里程碑来提供可能在所有方面都有效的临床前领先优势受隐孢子虫影响的患者群体，并具有适合婴儿治疗的安全特性，最小的药物间相互作用、最小的口服剂量要求、在热带地区的稳定性以及低制造成本。先导化合物优化方法结合了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，具有完善的药理学和药物学化学方法。为此，循环化学合成将与体外结合隐孢子虫检测、体外 ADME 研究、小鼠 PK 研究和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针对人型念珠菌的临床功效。药物的方法目标识别将利用先导化合物对抗相关疟疾寄生虫的活性识别与耐药性和候选药物靶标相关的突变，然后进行 CRISPR/Cas9 验证小隐孢子虫突变和评估直接蛋白质-药物相互作用的生化方法。成功将产生优化的临床候选药物，准备好进行监管测试毒理学研究和经过验证的药物靶点将通过基于靶点的方法加速药物开发药物设计和基于目标的筛选工作以确定其他化学型。鉴于迫切需要新的隐孢子虫病药物的成功对公众健康的影响可能极其重大。