Trehalose Pathway for Antifungal Targets and Inhibitors

摘要：项目3-抗真菌靶标和抑制剂的海藻糖途径 这个项目的中心是围绕着抗真菌靶标这一“圣杯”的特定靶标途径。 发展，包括与哺乳动物系统相比，目标真菌的重要专一性和 它的杀菌性能。在这项建议中，我们将扩展我们对新生隐球菌和念珠菌的研究 白念珠菌以前曾被用来仔细验证海藻糖途径在病毒性肺炎的病理生物学中的作用 这些担子菌和子囊菌。在其他主要的海藻糖途径中也有大量的数据 病原真菌，包括曲霉和毛霉，以及海藻糖抑制剂，也可以在这些地方进行研究。 霉菌。该提案主要分为两个主要重点，以加深对目标TPS 1的理解 (海藻糖-6-磷酸合成酶)和TPS-2(海藻糖-6-磷酸磷酸酶)，并鉴定抑制剂 将这些关键酶进一步开发成药物。在第一个目标中，将有一个详细的结构 对两种主要蛋白质的分析，以便对可能抑制的分子进行知情的研究 和/或与这些酶相互作用。结构/功能分析将允许开发屏幕以 从化学库中识别相互作用的分子。该提案的第二部分是开始一项 对抗性机制的理解(S)和识别相互作用或客户伙伴(蛋白质或 路径)。我们相信，这些策略可以优化这些海藻糖靶向 用于抗真菌的开发。第二个目标是对海藻糖进行全面的搜索和验证 具有评估其在动物身上的抗真菌活性的策略的抑制剂。有必要把重点放在杀菌上 活性、识别和使用协同靶标以提高杀菌活性和降低抗药性的能力 潜力。在我们看来，海藻糖途径是抗菌药物最重要的靶点之一。 研究，它仍然很不发达。它是体内真菌的极具杀菌力的靶标；它没有 在致病真菌王国中具有广谱意义，并且可以 延伸到影响人类疾病的其他微生物。

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.