IMPDH inhibitors for the treatment of Cryptosporidium infections

IMPDH 抑制剂用于治疗隐孢子虫感染

基本信息

批准号：
9156503
负责人：
Gregory D Cuny
金额：
$ 80.3万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9156503
关键词：
Acquired Immunodeficiency Syndrome Acute Acute Disease Address Adult Affect Animal Model Biological Assay Biological Warfare Bioterrorism Cause of Death Cell Culture Techniques Cells Child Chronic Chronic Disease Clinical Communities Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Cytosol Development Diarrhea Disease Outbreaks Drug Design Drug Exposure Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Enteral Enzymes Epidemic Epithelial Cells Evaluation Excretory function FDA approved Gastroenteritis Genes Genetic Genomics Goals Guanine Nucleotides Health Histopathology Horizontal Gene Transfer Human IMP Dehydrogenase Immunocompromised Host In Vitro Infection Interdisciplinary Study Intestinal parasite Intestines Malaria Mediating Metabolism Methods Modeling Multicenter Studies Mus Nucleotide Biosynthesis Oocysts Oral Organism Orthologous Gene Parasites Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Population Positioning Attribute Property Proteobacteria Purines Recycling Reporter Research Resistance Risk Rotavirus Series Solubility Terrorism Toxic effect Vaccine Therapy Vaccines Vacuole Water Supply Work absorption acute toxicity analog commensal microbes design drug development effective therapy fluorescence imaging functional group gastrointestinal gastrointestinal system improved in vivo in vivo Model in vivo imaging inhibitor/antagonist innovation mortality mouse model pathogen pre-clinical programs research study therapeutic development tool treatment strategy uptake water treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Cryptosporidium species, such as C. parvum, are protozoan parasites that present a significant health threat to young children and immunocompromised adults. These organisms are potential bio-terrorism agents that could incapacitate large populations, as well. Current treatment options for Cryptosporidium infections are limited. Commonly used anti-parasitic drugs are ineffective, the only FDA-approved drug is poorly efficacious, and vaccines are unavailable. Cryptosporidium species rely on inosine 5’-monophosphate dehydrogenase (IMPDH), as revealed by genomic analysis, for producing guanine nucleotides and, hence, survival. The parasite likely obtained its IMPDH gene from ε-proteobacterium, so C. parvum IMPDH (CpIMPDH) is highly diverged from the human orthologs. Consequently, selective CpIMPDH inhibitors may provide an effective strategy for the treatment of cryptosporidiosis with minimum toxicity to patients. To date, we have identified several structurally distinct classes of CpIMPDH inhibitors that have demonstrated excellent enzymatic potency, selectivity over human IMPDH, anti-parasitic activity in a cell culture model and, for one compound series, in vivo efficacy in an acute cryptosporidiosis mouse model. The overall goals of this study are to further refine CpIMPDH inhibitors to achieve efficacy in both acute and chronic mouse models of cryptosporidiosis to support the hypothesis that selective CpIMPDH inhibition is a viable treatment strategy for C. parvum infections, provide guidance for the research community with respect to optimal compound properties for in vivo efficacy and selection of pre-clinical candidates for further development. These goals will be achieved by pursuing three specific aims: 1) design and in vitro evaluation of CpIMPDH inhibitors in assays of CpIMPDH inhibitory potency and selectivity, a C. parvum cell culture infection model and ADME properties (including solubility, intestinal microsomal stability, cellular uptake, efflux, toxicity, and UGT-mediated glucuronidation); 2) assess the in vivo pharmacokinetic and acute toxicity properties of CpIMPDH inhibitors, including in vivo models of absorption and tissue distribution in both normal and C. parvum infected mice; 3) evaluate optimized CpIMPDH inhibitors in acute and chronic animal models of cryptosporidiosis assessing efficacy via imaging of fluorescent parasites, fecal oocyst excretion and gastrointestinal gross and histopathology. In addition, the impact of CpIMPDH inhibitors on commensal bacteria populations will be examined to more fully evaluate pharmacodynamics. This project will also develop a strategy for enterohepatic recycling in order to maximize gastrointestinal concentrations, while reducing systemic exposure and toxicity risk. 1

项目摘要/摘要隐孢子虫种类，例如C. parvum，是原生动物寄生虫，对幼儿和免疫功能低下的成年人。这些生物是潜在的生物恐怖剂也丧失了大量人群。当前的隐孢子虫感染的治疗选择受到限制。常用的抗寄生虫药物无效，唯一的FDA批准药物效率低下，并且疫苗不可用。隐孢子虫种类依赖于5'-单磷酸肌苷脱氢酶（IMPDH），如基因组分析所揭示的，用于产生鸟嘌呤核动肽及其生存。寄生虫可能是从ε-蛋白杆菌获得的IMPDH基因，因此C。parvum impdh（cpimpdh）高度与人类直系同源物不同。因此，选择性CPIMPDH抑制剂可能会提供有效的治疗隐孢子虫病的策略对患者的毒性最小。迄今为止，我们已经确定几种结构上不同的CPIMPDH抑制剂，它们表现出极好的酶促效力，对人IMPDH的选择性，细胞培养模型中的抗寄生活性，以及一种化合物序列，急性隐孢子虫病小鼠模型中的体内效率。这项研究的总体目标是进一步精炼CPIMPDH抑制剂以在隐孢子虫病的急性和慢性小鼠模型中达到效率支持选择性CPIMPDH抑制是可行的治疗策略的假设感染，为研究社区提供有关最佳复合特性的指导体内效率和临床前候选者的选择，以进一步发展。这些目标将通过追求三个具体目标：1）在CPIMPDH测定中对CPIMPDH抑制剂的设计和体外评估抑制效力和选择性，C。parvum细胞培养感染模型和ADME特性（包括溶解度，肠微粒体稳定性，细胞摄取，排出，毒性和UGT介导的葡萄糖醛酸化）； 2）评估CPIMPDH抑制剂的体内药代动力学和急性毒性特性，包括体内在正常和par虫感染小鼠中的抽象和组织分布模型； 3）评估了优化急性和慢性动物的CPIMPDH抑制剂通过成像评估有效性荧光寄生虫，粪便卵囊排泄和胃肠道的总体和组织病理学。另外，将检查CPIMPDH抑制剂对共生细菌种群的影响以更全面地评估药效学。该项目还将制定一种用于最大化的Enterohepati回收策略胃肠道浓度，同时减少全身暴露和毒性风险。 1