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.

项目概要 人类感染致病性自由生活的阿米巴原虫福氏耐格里阿米巴导致原发性原发性感染 阿米巴脑膜脑炎 (PAM)，大多数 (>95%) 感染以 致命性。我们最近发现了一组糖酵解的膦酸盐抑制剂 烯醇化酶（ENO）在哺乳动物中具有良好的耐受性，是有效的抗阿米巴药 化合物。该提案的目的是检验阿米巴 ENO 的假设 (NfENO) 是治疗开发和优化膦酸盐的一个有前景的靶点 抑制剂进入早期领先阶段。作为其中的一部分，我们将使用一小部分抑制剂和 一系列直系同源测定，以生物化学方式验证 NfENO 作为药物的靶标 将确定抑制剂对啮齿动物疾病模型中阿米巴原虫感染的影响， 作为努力的一部分，对治疗的免疫反应进行评分。