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

自噬机制已被证明可以调节宿主对各种感染性病原体的反应。这些反应包括通过典型的自噬对特定病原体的溶酶体降解，以及通过非降解途径依赖干扰素对其他病原体的杀伤。开发增强自噬(ATG)蛋白依赖途径的小分子可能有可能产生针对广泛生物体的治疗药物。拟议的项目应用下一代合成化学和高通量筛选来发现新的ATG介导的防御病原体感染的增强剂。该项目包括表型筛选和基于目标的筛选，以发现自噬和ATG依赖过程的调节器，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，以产生适合于在动物研究中测试治疗策略的治疗先导。

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.