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

基本信息

批准号：
8655106
负责人：
STUART L SCHREIBER
金额：
$ 202.68万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
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/8655106
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 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

项目摘要

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.

自噬机械已显示可针对各种传染剂进行介导宿主反应。这些反应包括通过规范自噬对特定病原体的溶酶体降解，以及通过非降解途径对其他病原体的干扰素依赖性杀害。开发出增强自噬（ATG）蛋白依赖性途径的小分子可能有可能对各种生物体产生治疗剂。拟议的项目采用下一代合成化学和高通量筛查，以发现对病原体感染的ATG介导的防御的新颖增强子。该项目包括表型和基于目标的筛选，以发现自噬和依赖ATG依赖性过程的调节剂，这些过程将对其活性进行测试，以针对NIAID感兴趣的一系列病原体。具有广泛活性的化合物的作用机制将被特征，并通过药物化学进一步开发，以产生适合于动物研究中测试治疗策略的治疗铅。