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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.

项目总结