Autophagy Modulators as Novel Broad-Spectrum Anti-Infective Agents

自噬调节剂作为新型广谱抗感染剂

• 批准号: 9010908
• 负责人: HERBERT W VIRGIN
• 金额: $ 669.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9010908
• 关键词: Animals; Anti-Infective Agents; Antithymoglobulin; Autophagocytosis; Bacteria; Bacterial Infections; Binding; Cell physiology; Chikungunya virus; Collaborations; Development; General Hospitals; Genes; Goals; Host Defense; Host resistance; Immune; Infection; Institutes; Instruction; Lead; Listeria monocytogenes; Lysosomes; Massachusetts; Medicine; Membrane; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Norovirus; Parasites; Pathway Analysis; Pathway interactions; Peptides; Play; Process; Proteins; Publications; Recording of previous events; Research Project Grants; Resistance to infection; Resources; Salmonella typhimurium; Staphylococcus aureus; Technology; Texas; Therapeutic; Toxoplasma gondii; Universities; Vesicle; Virus; Washington; West Nile virus; density; genetic analysis; medical schools; novel; pathogen; programs; protective effect; small molecule

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 w/e 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 co-publication. 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.

在这个 CETR 项目“自噬调节剂作为新型广谱抗感染剂”中，我们将 发现、验证和优化新型广谱抗感染药物。我们的方法将是加强 对多种 NIAID 优先病原体具有活性的宿主途径的抗感染功效。 自噬以及自噬相关基因（ATG 基因）在抵抗感染中的功能代表 这样的途径。自噬和 ATG 基因是针对病毒、细菌和细菌的免疫防御的核心。 寄生虫包括西尼罗河病毒、基孔肯雅病毒、诺如病毒、结核分枝杆菌、金黄色葡萄球菌、弓形虫、弓形虫、李斯特菌等。 单核细胞增生李斯特菌和鼠伤寒沙门氏菌，因此为广谱药物的开发提供了独特的靶标 抗感染剂。自噬是一种细胞过程，其中细胞质货物，包括 病原体和病原体成分​​被捕获在双层膜结合的囊泡内，以递送至 溶酶体和降解。 ATG 蛋白还可以通过以下过程在宿主防御中发挥关键作用： 不需要自噬途径。在此 CETR 计划中，我们将开发刺激 自噬和/或 ATG 基因作为广谱抗感染剂的活性。我们的主要交付成果将 是半优化的先导化合物，对动物具有针对多种病原体的保护作用。我们有 已经鉴定出一种自噬诱导肽，可以保护小鼠免受多种病毒的感染， 并完成了高密度化合物筛选，确定了自噬诱导分子 抑制细菌复制。我们将开发这些初始候选者，并将确定其他经过验证的候选者 进一步复合筛选的目标。我们的团队由该领域的专家组成，包括博士。跳过维珍，贝丝 Levine、Ramnik Xavier 和 Stuart Schreiber 是一个有着丰富合作和共同出版历史的团队。 为了实现我们的目标，我们将利用广泛的优秀设施和资源 研究所、马萨诸塞州总医院、华盛顿大学医学院和大学 德克萨斯州西南医学院。我们将通过四个研究项目来实现我们的目标， 管理核心，以及遗传和通路分析核心。我们的项目有：（1）自噬诱导 用于病毒治疗的肽和靶点识别（Levine）； (2) 自噬依赖的基因/通路 抑制细菌感染（Xavier）； (3) ATG基因依赖性抑制的基因/途径 病毒和寄生虫感染（处女）； (4) 增强 ATG 依赖性防御病原体 治疗性先导化合物（Schreiber）。通过关注自噬和ATG基因，并利用切割 边缘技术，我们的 CETR 团队将优化现有的治疗线索并提供一系列 开发一类新型广谱抗感染药物的新靶标。