Trehalose Pathway for Antifungal Targets and Inhibitors

抗真菌靶点和抑制剂的海藻糖途径

基本信息

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
项目类别：
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

项目摘要

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——抗真菌靶点和抑制剂的海藻糖途径该项目以包含抗真菌靶点“圣杯”的特定靶点途径为中心发育，其中包括与哺乳动物系统相比目标的重要真菌特异性和在本提案中，我们将扩展对新型隐球菌和念珠菌的研究。白色念珠菌，以前曾被用来仔细验证病理学中的海藻糖途径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数据。病原真菌包括曲霉属和毛霉属，因此海藻糖抑制剂也可以在这些中进行研究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-磷酸合酶）和 Tps 2（海藻糖-6-磷酸磷酸酶）并鉴定抑制剂第一个目标是研究这些关键酶的详细结构，并将其进一步开发为药物。分析两种主要蛋白质，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筛选。该提案的第二部分是开始研究化学库中的相互作用分子。了解耐药机制并识别相互作用或客户伙伴（蛋白质或我们相信这些策略可以优化这些海藻糖目标的实现方式。用于抗真菌开发的第二个目标是全面搜索和验证海藻糖。抑制剂及其在动物中评估其抗真菌活性的策略有必要关注杀菌作用。活性、识别和使用协同目标以提高杀菌活性和减少耐药性的能力我们认为，海藻糖途径是抗菌领域最重要的目标领域之一。它是一种对体内真菌具有极强杀灭作用的靶点；哺乳动物对应物；并且它在致病真菌界中具有广泛的意义，并且可以扩展到影响人类疾病的其他微生物。