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

项目概要/摘要隐孢子虫物种，例如小隐孢子虫，是原生动物寄生虫，对人类健康构成重大威胁幼儿和免疫功能低下的成年人这些生物体是潜在的生物恐怖分子。目前针对隐孢子虫感染的治疗选择也很有限。常用的抗寄生虫药物效果不佳，唯一FDA批准的药物疗效不佳，隐孢子虫物种依赖肌苷 5’-单磷酸脱氢酶，目前尚无疫苗。（IMPDH），正如基因组分析所揭示的，用于产生鸟嘌呤核苷酸，从而促进生存。寄生虫很可能从 ε-变形杆菌获得 IMPDH 基因，因此 C. parvum IMPDH (CpIMPDH) 高度与已测试的人类直系同源物不同，选择性 CpIMPDH 抑制剂可能提供有效的治疗。迄今为止，我们已经确定了对患者毒性最小的隐孢子虫病治疗策略。几类结构不同的 CpIMPDH 抑制剂已表现出优异的酶促作用效力、对人 IMPDH 的选择性、细胞培养模型中的抗寄生虫活性以及对于一种化合物系列，在急性隐孢子虫病小鼠模型中的体内疗效本研究的总体目标是进一步。改进 CpIMPDH 抑制剂以在急性和慢性隐孢子虫病小鼠模型中发挥功效支持以下假设：选择性 CpIMPDH 抑制是微小念珠菌的可行治疗策略感染，为研究界提供有关最佳化合物特性的指导这些目标将通过体内功效和临床前候选药物的选择来实现。追求三个具体目标：1) 在 CpIMPDH 测定中设计和体外评估 CpIMPDH 抑制剂抑制效力和选择性、C. parvum 细胞培养感染模型和 ADME 特性（包括溶解度、肠道微粒体稳定性、细胞摄取、流出、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，包括体内正常小鼠和微小念珠菌感染小鼠的吸收和组织分布模型；3) 评估优化后的模型； CpIMPDH 抑制剂在隐孢子虫病急性和慢性动物模型中通过成像评估疗效荧光寄生虫、粪便卵囊排泄以及胃肠道肉眼和组织病理学。将检查 CpIMPDH 抑制剂对共生细菌种群的影响，以更全面地评估该项目还将制定肠肝回收策略，以最大限度地发挥作用。胃肠道浓度，同时降低全身暴露和毒性风险。 1