IDENTIFICATION OF NEW DRUGS AGAINST AMEBIASIS

抗阿米巴病新药的鉴定

• 批准号: 8360070
• 负责人: AVELINA ESPINOSA
• 金额: $ 6.97万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360070
• 关键词: Alcohol dehydrogenase; Alcohols; Algae; Amebiasis; Amines; Antibiotics; Bacteria; Behavioral Research; Biochemical; Biomedical Research; Cause of Death; Clinical; Collaborations; Custom; Cyst; Data; Disease; Drug Design; Drug toxicity; EhADH2 enzyme; Entamoeba histolytica; Enzymes; Fermentation; Funding; Grant; Growth; Human; Iron; Laboratory Study; Life Cycle Stages; Marines; Molecular Models; National Center for Research Resources; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Population; Principal Investigator; Research; Research Infrastructure; Resources; Rhode Island; Source; Staging; Surveys; Symptoms; Testing; Toxic effect; United States National Institutes of Health; Universities; antimicrobial; cost; member; microbial; model design; molecular modeling; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Amebiasis is the second leading parasitic cause of death worldwide. 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 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 阿米巴病是全球第二大寄生虫死亡原因。其病原体是厌氧原生动物溶组织内阿米巴。世界上大约12%的人口被感染。每年有近 5000 万人出现临床症状，导致全球 10 万人死亡。有限的药物选择、药物毒性和疾病的侵袭性形式使治疗变得复杂。溶组织内阿米巴生命周期由致病滋养体阶段和传染性包囊阶段组成。我的实验室研究溶组织内阿米巴乙醇脱氢酶 2 (EhADH2)，它是糖酵解途径中的一种双功能酶。我们已经证明，这种酶对于溶组织内阿米巴滋养体的生长和生存至关重要。由于它是微生物组 III 或“铁激活”乙醇脱氢酶的成员，因此它与真核酶几乎没有同源性。这些发酵酶似乎是从细菌水平转移的。 ADHE 酶可能与脊椎动物酶具有不同的进化起源，这表明它们是潜在的抗菌靶点。使用市售环烷醇进行的初步测试显示，在预计对人类无毒的浓度下，EhADH2 活性和滋养体存活具有特异性抑制作用。我们目前正在测试胺、卤化物和叔醇。药物疗法的新颖搜索是使用三种策略来完成的：a）与罗德岛大学的 David Rowley 合作，测试从调查的纳拉甘西特湾海洋细菌和藻类中提取的抗生素提取物。 b) 与罗杰威廉姆斯大学的 Lauren Rossi 合作定制合成吡唑啉和其他对人类低毒性的有机化合物。 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。