Enolase inhibitors as therapeutic leads for Naegleria fowleri infections

烯醇酶抑制剂作为福氏耐格里阿米巴感染的治疗先导药物

• 批准号: 10739388
• 负责人: JAMES Culvin MORRIS
• 金额: $ 20.54万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739388
• 关键词: Amoeba genus; Animals; Biochemical; Biological Assay; Body Weight decreased; Cells; Chemicals; Collection; Continuous Infusion; Development; Disease model; Drug Design; Engineering; Enzyme Inhibition; Enzymes; Experimental Animal Model; Genetic; Glioblastoma; Goals; Human; Human Cell Line; Immune; Immune response; Immune system; In Vitro; Infection; Lead; Mammals; Medicine; Metabolic; Metabolism; Monitor; Naegleria; Naegleria fowleri; Outcome; Parasites; Parents; Pathogenicity; Pathologic; Pathway interactions; Phosphonic Acids; Probability; Protein Isoforms; Proteins; Proteome; Reagent; Rodent Diseases; Rodent Model; Role; Series; Specificity; Structure; Testing; Therapeutic; Time; Tissues; Toxic effect; Work; analog; cellular targeting; enolase; experimental study; glucose metabolism; improved; in vivo; inflammatory marker; inhibitor; insight; mortality; mouse model; neoplastic cell; nonhuman primate; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; phosphonate; primary amebic meningoencephalitis; targeted agent; targeted treatment; therapeutic development; therapeutic target; tool; treatment response

Project Summary Human infection by the pathogenic free-living amoeba Naegleria fowleri causes primary amebic meningoencephalitis (PAM), which in the majority (>95%) of infections end in fatality. We have recently found that a group of phosphonate inhibitors of the glycolytic enzyme enolase (ENO) that are well-tolerated in mammals are potent anti-amebic compounds. The goal of this proposal is to test the hypothesis that the amoeba ENO (NfENO) is a promising target for therapeutic development and to optimize phosphonate inhibtors to early lead stage. As part of this, we will use a small collection of inhibitors and a series of orthologous assays to biochemically validate NfENO as target of the agents and will determine the effect of the inhibitors on amoebae infections in a rodent disease model, scoring the immune response to treatment as part of the effort.

项目摘要 人类感染致病性自由生活的福氏耐格里阿米巴， 阿米巴脑膜脑炎（PAM），其中大多数（>95%）感染以 死亡我们最近发现一组糖酵解的膦酸盐抑制剂， 在哺乳动物中耐受良好的烯醇化酶（ENO）是有效的抗阿米巴 化合物.这个提议的目的是检验变形虫ENO （NfENO）是用于治疗开发和优化膦酸盐的有前途的靶点。 进入早期领先阶段作为其中的一部分，我们将使用一小部分抑制剂和 - 一系列的正磷酸酶测定，以生物化学验证NfENO作为试剂的靶标， 将确定抑制剂对啮齿动物疾病模型中阿米巴感染的作用， 对治疗的免疫反应进行评分作为努力的一部分。