IMPDH inhibitors for the treatment of Cryptosporidium infections

IMPDH 抑制剂用于治疗隐孢子虫感染

• 批准号: 9305043
• 负责人: Gregory D Cuny
• 金额: $ 75.99万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 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/9305043
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Acute Disease; Address; Adult; Affect; Alpha Cell; Animal Model; Antiparasitic Agents; Biological Assay; Biological Warfare; Bioterrorism; Cause of Death; Cell Culture Techniques; Cells; Child; Chronic; Chronic Disease; 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; Glucuronides; 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; Toxic effect; Vaccine Therapy; Vaccines; Vacuole; Water Supply; Work; absorption; acute toxicity; analog; clinical candidate; clinical development; commensal microbes; design; drug development; effective therapy; experimental study; 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; therapeutic development; tool; treatment strategy; uptake; water treatment

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

项目总结/文摘