Transdisciplinary Program to Identify Novel Antifungal Targets and Inhibitors

确定新型抗真菌靶点和抑制剂的跨学科计划

• 批准号: 9272329
• 负责人: John R. Perfect
• 金额: $ 180.35万
• 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/9272329
• 关键词: Address; Animal Disease Models; Animal Model; Animals; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus fumigatus; Biological; Biology; Body Temperature; Calcineurin Pathway; Candida; Candida albicans; Candida glabrata; Candidiasis; Carbohydrates; Cause of Death; Cell physiology; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Critical Pathways; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Crystallography; Custom; Development; Discipline; Elements; Evaluation; Fungal Proteins; Goals; Growth; Healthcare; High temperature of physical object; Human; Human body; Immunocompromised Host; In Vitro; Industrial fungicide; Industry Collaboration; Infection; Investigation; Knowledge; Lead; Libraries; Life; Link; Molecular; Molecular Target; Morphogenesis; Mucor; Mucormycosis; Mycoses; NMR Spectroscopy; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiology; Population; Positioning Attribute; Prevalence; Proteins; Resistance; Resolution; Scientist; Self Care; Signal Pathway; Signal Transduction; Stress; Structure; System; Testing; The science of Mycology; Therapeutic; Toxic effect; Translating; Trehalose; Virulence; Work; base; biological adaptation to stress; care burden; clinical application; clinical efficacy; cross reactivity; drug discovery; epidemiology study; experience; fungus; immunological status; improved; in vivo; inhibitor/antagonist; innovation; insight; novel; novel strategies; novel therapeutics; pathogen; programs; public health relevance; structural biology; targeted agent

 DESCRIPTION (provided by applicant): Transdisciplinary Program to Identify Novel Antifungal Targets This Program Project represents a unique, coordinated and synergistic strategy to discover novel antifungal drugs to effectively treat life-threatening invasive fungal infections. Invasive fungal infections remain a leading cause of death in the growing population of immunosuppressed patients. Presently, there are several classes of approved antifungal agents, but they suffer from limited clinical efficacy, reduced fungicidal activity in the host, debilitating toxicity profiles, and/or emergence of resistance. To identify innovative antifungal targets and agents, we have merged the disciplines of structural biology, molecular mycology, and vertebrate pathology with our clinical insights and experience to produce a novel direction for antifungal development. This focus targets three cell signaling pathways critical to the capability of pathogenic fungi to survive and grow at human body temperature (37°C). Our previous studies have identified and carefully validated these signal transduction circuits that enable high temperature growth at 37°C and virulence for the three major fungal pathogens (Candida, Aspergillus, Cryptococcus). These three pathways are: (1) the calcineurin pathway, a conserved pathway for fungal virulence; (2) the Ras pathway, which governs fungal morphogenesis and stress responses; and (3) the trehalose pathway, which synthesizes a fungal specific thermoprotective carbohydrate and other stress protectants. Our work to date has also identified key interconnections among these pathways, which we will further investigate for synergistic therapeutic potential. Our overall hypothesis is that by applying structural biologc approaches to rigorous investigations in mycology, we will define critical, targetable differences between key fungal proteins required for thermotolerance and the proteins' mammalian counterparts, creating a therapeutic platform on which to develop novel fungal-specific inhibitors that lack mammalian cross-reactivity. Our overall aims are to: (1) define fungal-specific structural differences in the three signaling pathways, (2) generate novel inhibitors against these signaling pathways and optimize their entry into fungal cells, and (3) test inhibitors for in vitro and in vivo biological activity. To accomplish these Aims, we propose three linked Projects and three supporting Cores. The impact of this novel approach will be to identify and validate potent fungal-specific inhibitors of these critical signaling pathways that can be further translated for clinical application by our industry collaborators to drugs to improve patient outcome.

 描述（由申请人提供）：确定新型抗真菌靶点的跨学科计划该计划代表了一种独特、协调和协同的策略，旨在发现新型抗真菌药物，以有效治疗危及生命的侵袭性真菌感染。侵袭性真菌感染仍然是导致死亡的主要原因。目前，有几类已批准的抗真菌药物，但它们的临床疗效有限，对宿主的杀真菌活性降低，毒性减弱。为了确定创新的抗真菌靶标和药物，我们将结构生物学、分子真菌学和脊椎动物病理学学科与我们的临床见解和经验相结合，为抗真菌开发提供了一个新的方向。我们之前的研究已经识别并仔细验证了这些能够在 37°C 和 37°C 高温下生长的信号转导通路。三种主要真菌病原体（念珠菌、曲霉、隐球菌）的毒力这三种途径是：(1) 钙调神经磷酸酶途径，是真菌毒力的保守途径；(2) Ras 途径，控制真菌形态发生和应激反应； （3）海藻糖途径，合成真菌特异性热保护碳水化合物和其他应激保护剂，迄今为止我们的工作还确定了这些途径之间的关键相互联系。我们将进一步研究这些途径的协同治疗潜力，我们的总体假设是，通过将结构生物学方法应用于真菌学的严格研究，我们将定义耐热性所需的关键真菌蛋白与蛋白质的哺乳动物移植物之间的关键的、可靶向的差异，从而创造出耐热性所需的关键真菌蛋白。一个开发缺乏哺乳动物交叉反应性的新型真菌特异性抑制剂的治疗平台，我们的总体目标是：(1) 定义三种信号通路中真菌特异性的结构差异，(2) 产生针对这些信号通路的新型抑制剂。 信号通路并优化其进入真菌细胞，以及（3）体外测试抑制剂 为了实现这些目标，我们提出了三个相互关联的项目和三个支持核心，这种新方法的影响将是识别和验证这些关键信号通路的有效真菌特异性抑制剂，这些抑制剂可以进一步转化为临床。我们的行业合作者将其应用于药物以改善患者的治疗效果。