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）：