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：
10356051
负责人：
CHRISTOPHER D HUSTON
金额：
$ 69.75万
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/10356051
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 porcine model 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具有两种隐孢子虫寄生虫之一，分别是C. parvum或C. hominis。 Nitazoxanide是唯一的批准药物，在其他健康的成年人中有效，但不幸的是，儿童的功效（约56％），相当于艾滋病患者的安慰剂。这项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，寄生虫哌嗪 - 通过表型筛选确定的具有非凡体内功效的基于非凡的铅化合物将是优化及其分子作用机理将被确定。铅优化计划是指导的通过理想的目标产品概况和里程碑，提供了可能在所有人方面有效的临床前潜在客户受隐孢子虫影响并具有适合治疗婴儿的安全特征的患者人群，最小的药物相互作用，最小的口服剂量要求，热带地区的稳定性和低制造成本。铅优化的方法将新颖的体外测定和高度具有公认的药理学和药理学的隐孢子虫病的免疫功能低下的小鼠模型化学方法。为此，化学合成的环状圆将与体外结合隐孢子虫测定，体外ADME研究，小鼠PK研究和慢性小鼠C. parvum 感染。然后，将使用小猪模型来测试针对hominis的临床功效。药物的方法靶标识别将利用铅化合物对相关疟疾寄生虫的活性确定与耐药性和候选药物靶标相关的突变，其次是CRISPR/CAS9 验证Parvum C. parvum和生化方法中的突变，以评估直接蛋白质 - 药物相互作用。成功将产生优化的临床候选者，该临床候选者准备在调节中进行测试毒理学研究，以及经过验证的药物靶标，可以通过基于靶向目标来加速药物开发药物设计和基于目标的筛查工作以鉴定其他化学型。考虑到新的需求隐孢子虫病药物，成功的公共卫生影响可能非常重要。