Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents

描述（由申请人提供）： 在这个CETR计划中，“自噬调节剂作为新型广谱抗感染药物”，我们将发现，验证和优化新型广谱抗感染药物。我们的方法将是增强对广泛的NIAID优先病原体具有活性的宿主途径的抗感染功效。自噬和自噬相关基因（ATG基因）在抵抗感染中的功能代表了这样的途径。自噬和ATG基因是针对病毒、细菌和寄生虫的免疫防御的核心，所述寄生虫包括西尼罗河病毒、基孔肯雅病毒、诺如病毒、M. tuberculosis，S. aureus，T. gondii，L.单核细胞增多症和S.因此为开发广谱抗感染剂提供了独特的靶标。自噬是一种细胞过程，其中细胞质货物，包括病原体和病原体组分，被捕获在双膜结合囊泡内，用于递送到溶酶体并降解。ATG蛋白也可以通过不需要自噬途径的过程在宿主防御中发挥关键作用。在这个CETR计划中，我们将开发刺激自噬和/或ATG基因活性的小分子作为广谱抗感染剂。我们的主要成果将是半优化的先导化合物，对动物具有保护作用，可抵御一系列病原体。我们已经确定了一种自噬诱导肽，可以保护小鼠免受各种病毒的感染，并完成了高密度化合物筛选，确定了抑制细菌复制的自噬诱导分子。我们将开发这些初步候选药物，并将为进一步的化合物筛选确定其他经验证的靶标。我们的团队结合了该领域的专家，包括Skip Virgin博士，Beth Levine，Ramnik Xavier和Stuart Schreiber，这是一个具有广泛合作和共同出版历史的团队。为了实现我们的目标，我们将利用布罗德研究所、马萨诸塞州总医院、华盛顿大学医学院和德克萨斯大学西南医学院的优秀设施和资源。我们将通过四个研究项目，行政核心，遗传和途径分析核心来实现我们的目标。我们的项目包括：（1）用于治疗病毒的自噬诱导肽和靶标鉴定（Levine）;（2）用于细菌感染的自噬依赖性抑制的基因/途径（Xavier）;（3）用于病毒和寄生虫感染的ATG基因依赖性抑制的基因/途径（Virgin）;和（4）用治疗性先导化合物增强针对病原体的ATG依赖性防御（Schreiber）。通过专注于自噬和ATG基因，并使用尖端技术，我们的CETR团队将优化现有的治疗线索，并为开发一类新的广谱抗感染药物提供新的靶点。

DESCRIPTION (provided by applicant): In this CETR program, 'Autophagy Modulators as Novel Broad-Spectrum Anti-infective Agents', we will discover, validate, and optimize novel broad-spectrum anti-infective agents. Our approach will be to enhance the anti-infective efficacy of a host pathway that is active against a wide range of NIAID priority pathogens. Autophagy and the function of autophagy-related genes (ATG genes) in resistance to infection represent such a pathway. Autophagy and ATG genes are central to immune defense against viruses, bacteria, and parasites including West Nile virus, chikungunya virus, norovirus, M. tuberculosis, S. aureus, T. gondii, L. monocytogenes, and S. typhimurium and therefore provide unique targets for the development of broad spectrum anti-infective agents. Autophagy is a cellular process in which cytoplasmic cargo, including pathogens and pathogen components, are captured within a double membrane-bound vesicle for delivery to the lysosome and degradation. ATG proteins can also play key roles in host defense via processes that do not require the autophagy pathway. In this CETR program we will develop small molecules that stimulate the activity of autophagy and/or ATG genes as broad-spectrum anti-infective agents. Our main deliverable will be semi-optimized lead compounds with protective effects in animals against a range of pathogens. We have already identified an autophagy-inducing peptide that protects mice against infection with diverse viruses, and have completed a high-density compound screen that has identified autophagy-inducing molecules that inhibit bacterial replication. We will develop these initial candidates, and will identify additional validated targets for further compound screens. Our team combines experts in the field including Drs. Skip Virgin, Beth Levine, Ramnik Xavier, and Stuart Schreiber, a group with an extensive history of collaboration and copublication. To accomplish our goals we will leverage the outstanding facilities and resources of the Broad Institute, the Massachusetts General Hospital, Washington University School of Medicine, and the University of Texas Southwestern Medical School. We will accomplish our goals through four Research Projects, an Administrative Core, and a Genetic and Pathway Analysis Core. Our Projects are: (1) Autophagy-Inducing Peptides and Target Identification for Treatment of Viruses (Levine); (2) Genes/Pathways for Autophagy dependent Inhibition of Bacterial Infection (Xavier); (3) Genes/Pathways for ATG Gene-dependent Inhibition of Virus and Parasite Infection (Virgin); and (4) Enhancing ATG-dependent Defense Against Pathogens with Therapeutic Lead Compounds (Schreiber). By focusing on autophagy and ATG genes, and using cutting edge technologies, our CETR team will optimize already existing therapeutic leads and provide a pipeline of novel targets for the development of a new class of broad-spectrum anti-infective medicines.