IDENTIFICATION OF NEW DRUGS AGAINST AMEBIASIS

抗阿米巴病新药的鉴定

• 批准号: 8167606
• 负责人: AVELINA ESPINOSA
• 金额: $ 6.84万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167606
• 关键词: Alcohol dehydrogenase; Alcohols; Algae; Amebiasis; Amines; Antibiotics; Bacteria; Biochemical; Cause of Death; Clinical; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Custom; Cyst; Data; Disease; Drug Design; Drug toxicity; EhADH2 enzyme; Entamoeba histolytica; Enzymes; Fermentation; Funding; Grant; Growth; Human; Institution; Iron; Laboratory Study; Life Cycle Stages; Marines; Molecular Models; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Population; Research; Research Personnel; Resources; Rhode Island; Source; Staging; Surveys; Symptoms; Testing; Toxic effect; United States National Institutes of Health; Universities; antimicrobial; member; microbial; molecular modeling; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amebiasis is the second leading parasitic cause of death worldwide and its causative agent is the anaerobic protozoan Entamoeba histolytica. Approximately 12% of the world's population is infected. Clinical symptoms manifest in nearly 50 million people annually, causing 100,000 fatalities worldwide. Limited drug options, drug toxicities, and invasive forms of the disease complicate treatment. Entamoeba histolytica's life cycle consists of the disease-causing trophozoite stage and the infectious cyst stage. My laboratory studies Entamoeba histolytica alcohol dehydrogenase 2 (EhADH2), a bifunctional enzyme in the glycolytic pathway. We have shown that this enzyme is essential for the growth and survival of E. histolytica trophozoites. As it is a member of the microbial group III or "iron activated" alcohol dehydrogenases it has little homology to eukaryotic enzymes. These fermentation enzymes appear to have been transferred horizontally from bacteria. ADHE enzymes likely different evolutionary origin from vertebrate enzymes suggests them as potential antimicrobial targets. Initial testing with commercially available cycloalkanols showed specific inhibition of EhADH2 activities and trophozoite survival at concentrations expected to be non-toxic to humans. We are currently testing amines, halides and tertiary alcohols. Novel searching of drug therapies is done using three strategies: a) test antibiotic extracts from surveyed Narragansett Bay marine bacteria and algae in collaboration with David Rowley, University of Rhode Island. b) custom-synthesis of pyrazoline and other organic compounds with low toxicity to humans in collaboration with Lauren Rossi, Roger Williams University. c) Biochemical and mutational analysis of EhADH2 to obtain structural/functional data for molecular modeling and drug design.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 Amebiasis是全世界死亡的第二大寄生虫原因，其致病药物是厌氧原生动物的溶作综合症。世界上约有12％的人口感染。临床症状每年在近5000万人中表现出来，在全球造成100,000人死亡。有限的药物选择，药物毒性以及疾病的侵入性形式使治疗复杂。 Entamoeba Histolictica的生命周期由引起疾病的滋养体阶段和感染性囊肿阶段组成。我的实验室研究在糖酵解途径中纳入了溶液性溶质醇脱氢酶2（EHADH2），这是一种双功能酶。我们已经表明，这种酶对于组织溶解性大肠杆菌滋养体的生长和存活至关重要。由于它是微生物III或“铁激活”醇脱氢酶的成员，因此与真核酶的同源性很小。这些发酵酶似乎已经从细菌水平转移。 ADHE酶可能与脊椎动物酶不同的进化起源表明它们是潜在的抗菌靶标。用市售环烷醇的初步测试显示，在预期对人类无毒的浓度下，对EHADH2活性和滋养体生存的特异性抑制作用。我们目前正在测试胺，卤化物和三级醇。药物疗法的新颖搜索是使用三种策略进行的：a）与罗德岛大学的戴维·罗利（David Rowley）合作，调查的纳拉甘西特湾海洋细菌和藻类进行了测试抗生素提取物。 b）与劳伦·罗西（Lauren Rossi）合作的吡唑啉和其他有机化合物的定制合成，对人类的毒性低。 c）Ehadh2的生化和突变分析，以获得用于分子建模和药物设计的结构/功能数据。