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

自噬机制已被证明介导宿主对多种感染因子的反应。这些反应包括通过典型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伤。开发增强自噬（ATG）蛋白依赖途径的小分子可能有潜力产生针对广泛生物体的治疗方法。该项目应用新一代合成化学和高通量筛选来发现atg介导的病原体感染防御的新型增强子。该项目包括表型和基于靶标的筛选，以发现自噬和atg依赖过程的调节剂，将测试它们对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以其作用机制为特征，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。

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.