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)： 在这个名为“自噬调节剂作为新型广谱抗感染药物”的CETR项目中，我们将发现、验证和优化新型广谱抗感染药物。我们的方法将是增强宿主途径的抗感染效果，该宿主途径对广泛的NIAID优先病原体具有活性。自噬和自噬相关基因(ATG基因)在抵抗感染方面的功能就是这样一条途径。自噬和ATG基因是针对病毒、细菌和寄生虫(包括西尼罗河病毒、基孔肯雅病毒、诺沃克病毒、结核分枝杆菌、金黄色葡萄球菌、弓形虫、单核细胞增多症和鼠伤寒沙门氏菌)的免疫防御的核心，因此为广谱抗感染药物的开发提供了独特的靶点。自噬是一种细胞过程，在这个过程中，细胞质货物，包括病原体和病原体成分，被捕获在一个双层膜结合的小泡中，运送到溶酶体并降解。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，我们将开发小分子来刺激自噬和/或ATG基因的活性，作为广谱抗感染药物。我们的主要产品将是半优化的先导化合物，对动物具有保护作用，抵御一系列病原体。我们已经确定了一种自噬诱导肽，可以保护小鼠免受不同病毒的感染，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。我们将开发这些初始候选，并将为进一步的复合筛选确定更多已验证的目标。我们的团队汇集了该领域的专家，包括Skip Virgin博士、Beth Levine博士、Ramnik Xille博士和Stuart Schreiber博士，他们有着广泛的合作和沟通历史。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卓越设施和资源。我们将通过四个研究项目实现我们的目标，一个是行政核心，一个是遗传和通径分析核心。我们的项目是：(1)用于治疗病毒的自噬诱导肽和靶标识别(Levine)；(2)依赖自噬抑制细菌感染的基因/途径(Xavier)；(3)依赖ATG基因抑制病毒和寄生虫感染的基因/途径(Virgin)；以及(4)使用治疗性先导化合物增强ATG依赖的对病原体的防御(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，并为开发新型广谱抗感染药物提供一系列新的靶点。