Trehalose Pathway for Antifungal Targets and Inhibitors

抗真菌靶点和抑制剂的海藻糖途径

• 批准号: 8931205
• 负责人: RICHARD GERALD BRENNAN
• 金额: $ 57.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-25 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931205
• 关键词: Affect; Animal Model; Animals; Antifungal Agents; Antifungal Therapy; Area; Ascomycota; Aspergillus; Attenuated; Basidiomycota; Belief; Binding; Biology; Body Temperature; Calcineurin; Candida; Candida albicans; Cells; Cessation of life; Client; Coupled; Critical Pathways; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Data; Development; Disease; Drug Design; Drug Kinetics; Drug Targeting; Enzymes; Fungal Proteins; Genes; Goals; Growth; High temperature of physical object; Human; Human body; In Vitro; Industrial fungicide; Infection; Knowledge; Lead; Maps; Microbe; Modeling; Molds; Mucor; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Plants; Positioning Attribute; Preclinical Drug Evaluation; Property; Proteins; Research; Resistance; Resolution; Site; Specificity; Structural Protein; Structure; System; Temperature; Testing; Toxic effect; Trehalose; Validation; Work; analog; antimicrobial; design; drug development; enzyme pathway; fungus; human disease; improved; in vivo; inhibitor/antagonist; inorganic phosphate; mutant; novel; pathogen; programs; protein protein interaction; protein structure; resistance mechanism; small molecule libraries; trehalose-6-phosphate synthase

ABSTRACT: Project 3 – Trehalose Pathway for Antifungal Targets and Inhibitors This project is centered on a specific target pathway that encompasses the “holy grail” of antifungal target development which includes the important fungal specificity of the target compared to mammalian system and its fungicidal properties. In this proposal, we will extend our studies in Cryptococcus neoformans and Candida albicans which have been previously used to carefully validate the trehalose pathway in the pathobiology of these basidiomycetes and ascomycetes. There is also substantial data for trehalose pathway in other major pathogenic fungi including Aspergillus and Mucor and thus trehalose inhibitors could also be studied in these moulds. This proposal is primarily split into two major foci to develop understanding of the targets Tps 1 (Trehalose-6-phosphate synthase) and Tps 2 (Trehalose-6- phosphate phosphatase) and to identify inhibitors of these critical enzymes to further develop them into drugs. In the first aim, there will be a detailed structure analysis of the two major proteins to allow an informed approach to molecules which could potentially inhibit and/or interact with these enzymes. A structural/functional analysis will allow for development of screens to identify interacting molecules from chemical libraries. A second part of this proposal is to begin an understanding of resistance mechanism(s) and identification of interacting or client partners (proteins or pathways). It is our belief that these strategies allow an optimization of how these trehalose targets can be used for antifungal development. The second aim will be a comprehensive search and validation of trehalose inhibitors with strategies to evaluate their antifungal activity in animals. It is necessary to focus on fungicidal activity, ability to identify and use synergistic targets to improve fungicidal activity and reduce resistance potential. In our opinion the trehalose pathway represents one of the foremost target areas in antimicrobial research and it remains poorly developed. It is an extremely fungicidal target for fungi in vivo; it has no mammalian counterpart; and it has wide spectrum significance in the pathogenic fungal kingdom and can extend to other microbes impacting human disease.

摘要：项目3 - 抗真菌靶标和抑制剂的海藻糖途径 该项目以特定目标途径为中心，该途径涵盖了抗真菌目标的“圣杯” 与哺乳动物系统相比，包括目标的重要真菌特异性的开发 它的真菌特性。在此提案中，我们将扩展我们在加密赛和念珠菌的研究 白色 这些碱性菌和子囊菌。还有其他主要的海藻糖途径的大量数据 包括曲霉和粘膜在内的致病真菌，因此也可以在这些抑制剂中进行研究 模具。该建议主要分为两个主要焦点，以发展对目标TPS 1的理解 （三核-6-磷酸合酶）和TPS 2（三核-6-磷酸磷酸酶），并鉴定抑制剂 在这些关键酶中，将它们进一步发展为药物。在第一个目标中，将有一个详细的结构 分析两种主要蛋白质，以允许对分子的知情方法有可能抑制 和/或与这些酶相互作用。结构/功能分析将允许开发屏幕 从化学文库中确定相互作用的分子。该提议的第二部分是开始 了解抵抗机制以及识别相互作用或客户伙伴的识别（蛋白质或 途径）。我们认为这些策略允许对这些海藻糖的目标进行优化 用于抗真菌发育。第二个目标将是对海藻糖的全面搜索和验证 具有评估动物抗真菌活性的策略的抑制剂。有必要专注于真菌 活动，识别和使用协同目标以改善杀真菌活动并降低阻力的能力 潜在的。我们认为，海藻糖途径代表了抗菌剂的外国目标领域之一 研究，它的发展仍然很差。它是真菌在体内的极具真菌靶标。它没有 哺乳动物对应物；它在致病真菌王国中具有广泛的意义，可以 扩展到影响人类疾病的其他微生物。