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: 8642370
• 负责人: HERBERT W VIRGIN
• 金额: $ 637.76万
• 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/8642370
• 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; Immune; Infection; Institutes; 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; 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

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.

描述（由申请人提供）： 在这个CERT的程序中，“自动噬调节剂是新型的广谱抗感染剂”，我们将发现，验证和优化新型的广谱抗感染剂。我们的方法是增强宿主途径的抗感染功效，该宿主途径对广泛的NIAID优先病原体有效。自噬和自噬相关基因（ATG基因）对感染的抗性的功能代表了这种途径。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，包括西尼罗河病毒，chikungunya病毒，Norovirus，M。tuberculosis，S。aureus，T。Gondii，L。单核细胞增生和单核细胞增生和typhimurium S. typhimurium，因此为广阔的景点Antections开发了独特的目标。自噬是一种细胞过程，其中包括病原体和病原体成分​​在内的细胞质货物被捕获在双膜结合的囊泡中，以递送至溶酶体和降解。 ATG蛋白还可以通过不需要自噬途径的过程在主机防御中发挥关键作用。在此CERT计划中，我们将开发小分子，以刺激自噬和/或ATG基因作为广谱抗感染剂的活性。我们的主要可交付方式将是半优化的铅化合物，对动物的病原体具有保护作用。我们已经确定了一种自噬诱导肽，可保护小鼠免受各种病毒感染的感染，并完成了一个高密度化合物筛选，该筛选已鉴定出抑制细菌复制的自噬诱导分子。我们将开发这些初始候选者，并将确定进一步化合物屏幕的其他验证目标。我们的团队结合了该领域的专家，包括Drs。跳过Virgin，Beth Levine，Ramnik Xavier和Stuart Schreiber，这是一个拥有丰富合作和录取史的小组。为了实现我们的目标，我们将利用Broad Institute，马萨诸塞州综合医院，华盛顿大学医学院和德克萨斯大学西南医学院的杰出设施和资源。我们将通过四个研究项目，一个行政核心以及遗传和途径分析核心来实现我们的目标。我们的项目是：（1）自噬诱导肽和用于治疗病毒的靶标识别（莱文）； （2）自噬依赖性细菌感染的基因/途径（Xavier）； （3）ATG基因依赖性抑制病毒和寄生虫感染的基因/途径（Virgin）； （4）用治疗性铅化合物（Schreiber）增强针对病原体的ATG依赖性防御。通过专注于自噬和ATG基因，并使用尖端技术，我们的CERT团队将优化现有的治疗铅，并为开发新的广谱抗感染药物提供新的目标。