Enhancing ATG-dependent Defense Against Pathogens w/Therapeutics Lead CP

使用先导 CP 治疗增强 ATG 依赖性的病原体防御

• 批准号: 9010913
• 负责人: STUART L SCHREIBER
• 金额: $ 190.95万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9010913
• 关键词: Adverse effects; Affinity Chromatography; Animal Experiments; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antiviral Agents; Autophagocytosis; Bacterial Infections; Biological Assay; Cell Count; Cells; Chemicals; Chikungunya virus; Collaborations; Collection; Communicable Diseases; Communities; Databases; Dependence; Development; Disease; Enhancers; Gene Expression; Goals; Immune response; In Vitro; Infection; Infectious Agent; Institutes; Interferons; Knock-out; Lead; Listeria monocytogenes; Lysosomes; Mediating; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Norovirus; Organism; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Proteins; Proteomics; RNA interference screen; Research; Research Personnel; Route; Salmonella typhimurium; Series; Solubility; Structure-Activity Relationship; Synthesis Chemistry; Testing; Therapeutic; Toxoplasma gondii; Virus Diseases; West Nile virus; analog; base; cell type; clinically relevant; drug discovery; high throughput screening; in vitro Assay; in vivo; inhibitor/antagonist; interest; killings; member; next generation; novel; pathogen; pre-clinical; prevent; protein protein interaction; response; screening; small molecule; therapeutic development; tool; treatment strategy

The autophagy machinery has been shown to mediate host responses against a variety of infectious agents. These responses include the lysosomal degradation of specific pathogens via canonical autophagy, as well interferon-y-dependent killing of other pathogens via non-degradative pathways. Developing small molecules that enhance autophagy (ATG) protein-dependent pathways may have the potential to yield therapeutics against a broad spectrum of organisms. The proposed project applies next-generation synthetic chemistry and high-throughput screening to discover novel enhancers of ATG-mediated defense to pathogen infection. The project includes both phenotypic and target-based screens to discover modulators of autophagy and ATG-dependent processes, which will be tested for their activity against a range of pathogens of interest to the NIAID. Compounds with broad activity will be characterized for their mechanisms-of-action and developed further through medicinal chemistry to yield therapeutic leads suitable for testing treatment strategies in animal studies.

自噬机制已被证明可以介导宿主对多种传染性病原体的反应。这些反应包括特定病原体通过典型自噬的溶酶体降解，以及通过非降解途径的干扰素-γ依赖性杀死其他病原体。开发增强自噬（ATG）蛋白依赖性途径的小分子可能具有产生针对广谱生物体的治疗剂的潜力。该项目应用下一代合成化学和高通量筛选来发现ATG介导的防御病原体感染的新型增强剂。该项目包括基于表型和靶点的筛选，以发现自噬和ATG依赖性过程的调节剂，这些调节剂将被测试其对NIAID感兴趣的一系列病原体的活性。具有广泛活性的化合物将根据其作用机制进行表征，并通过药物化学进一步开发，以产生适合在动物研究中测试治疗策略的治疗线索。