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。 自噬和自噬相关基因（ATG基因）在抵抗感染中的功能代表了 这样一条路。自噬和ATG基因是针对病毒、细菌和病毒的免疫防御的核心。 寄生虫包括西尼罗河病毒、基孔肯雅病毒、诺如病毒、M.结核S. aureus，T. gondii，L. 单核细胞增多症和S.鼠伤寒沙门氏菌，因此为开发广谱 抗感染剂。自噬是一种细胞过程，其中细胞质货物，包括 病原体和病原体组分被捕获在双膜结合囊泡内， 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。在这个CETR计划中，我们将开发小分子， 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，在动物中对一系列病原体具有保护作用。我们有 已经发现了一种自噬诱导肽，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，确定了自噬诱导分子， 抑制细菌复制。我们将开发这些初步候选人，并将确定其他验证 进一步筛选化合物的目标。我们的团队结合了该领域的专家，包括Skip Virgin，Beth Levine，Ramnik Xavier和Stuart Schreiber，一个拥有广泛合作和共同出版历史的团队。 为了实现我们的目标，我们将充分利用远大卓越的设施和资源， 研究所、马萨诸塞州总医院、华盛顿大学医学院和大学 德克萨斯西南医学院的毕业生我们将通过四个研究项目来实现我们的目标， 管理核心，以及遗传和途径分析核心。我们的研究项目有：（1）诱导自噬 用于治疗病毒的肽和靶点鉴定（Levine）;（2）自噬依赖性细胞因子的基因/途径 抑制细菌感染（Xavier）;（3）用于ATG基因依赖性抑制的基因/途径 病毒和寄生虫感染（处女）;和（4）增强对病原体的ATG依赖性防御， 治疗性先导化合物（Schreiber）。通过关注自噬和ATG基因， 边缘技术，我们的CETR团队将优化现有的治疗线索，并提供 开发新的广谱抗感染药物的新靶点。