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 该项目是围绕一个特定的目标途径，包括“圣杯”的抗真菌药物的目标 发展，其中包括重要的真菌特异性的目标相比，哺乳动物系统和 它的杀菌特性。在这个建议中，我们将扩大我们的研究，在新型隐球菌和念珠菌 白色念珠菌，以前已被用来仔细验证海藻糖途径的病理生物学， 这些担子菌和子囊菌。在其他主要的哺乳动物中也有大量的海藻糖途径的数据。 病原真菌包括曲霉和毛霉，因此海藻糖抑制剂也可以在这些研究中进行研究。 霉菌。本建议主要分为两个重点，以加深对目标Tps 1的了解 （海藻糖-6-磷酸合酶）和Tps 2（海藻糖-6-磷酸磷酸酶），并鉴定抑制剂 这些关键酶来进一步将它们开发成药物。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，以了解可能抑制 和/或与这些酶相互作用。结构/功能分析将允许开发屏幕， 从化学文库中识别相互作用的分子。这项建议的第二部分是开始一项 了解耐药机制和识别相互作用或客户伙伴（蛋白质或 路径）。我们相信，这些策略允许优化这些海藻糖靶点如何能够被 用于开发抗真菌药物。第二个目标是对海藻糖进行全面的研究和验证 抑制剂与策略，以评估其在动物中的抗真菌活性。有必要重点关注杀菌剂 活性、鉴定和使用协同靶标以提高杀真菌活性和降低抗性的能力 潜力我们认为，海藻糖途径代表了抗微生物药物的最重要的目标领域之一。 研究，但仍不发达。它是体内真菌的一个非常杀真菌的靶标;它没有 哺乳动物对应物;并且它在致病真菌王国中具有广谱意义， 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.