Transdisciplinary Program to Identify Novel Antifungal Targets and Inhibitors

 描述(由申请人提供)：确定新的抗真菌靶点的跨学科计划该计划项目代表了一种独特、协调和协同的战略，以发现有效治疗危及生命的侵袭性真菌感染的新型抗真菌药物。侵袭性真菌感染仍然是日益增长的免疫抑制患者死亡的主要原因。目前，已批准的抗真菌药物有几类，但它们的临床疗效有限，在宿主中的杀菌活性降低，毒性减弱，和/或出现耐药性。为了确定创新的抗真菌靶点和药物，我们将结构生物学、分子真菌学和脊椎动物病理学的学科与我们的临床见解和经验相结合，为抗真菌的发展创造了一个新的方向。这一重点针对三个细胞信号通路，这些信号通路对病原真菌在人体温度(37摄氏度)下生存和生长的能力至关重要。我们之前的研究已经确定并仔细验证了这些信号转导电路，这些信号转导电路能够在37℃下高温生长，并对三种主要真菌病原体(念珠菌、曲霉、隐球菌)具有毒力。这三个途径是：(1)钙调神经磷酸酶途径，真菌毒力的保守途径；(2)RAS途径，调控真菌的形态发生和胁迫反应；(3)海藻糖途径，合成真菌特有的热保护碳水化合物和其他应激保护剂。到目前为止，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，我们将确定耐热性所需的关键真菌蛋白质与哺乳动物蛋白质之间的关键、有针对性的差异，从而创建一个治疗平台，在此平台上开发缺乏哺乳动物交叉反应的新型真菌特异性抑制剂。我们的总体目标是：(1)确定三个信号通路中真菌特有的结构差异；(2)产生针对这些信号通路的新型抑制剂 信号通路及其进入真菌细胞的优化，以及(3)体外试验抑制剂 和体内生物活性。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。这一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，这些抑制剂可以由我们的行业合作伙伴进一步转化为临床应用，以改善患者的预后。

 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.