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.
The development of therapeutics that prevent or treat infection by a broad range of pathogens is an urgent and unmet need for drug discovery. A drug that enhances the inherent ability of infected cells to clear pathogens within them may form the basis of a broad spectrum therapy, and represents a promising but untested strategy. The leads discovered in this project will enable the academic and pharmaceutical research communities to test, in animals, whether specific defense pathways (canonical and non-canonical autophagy) can be exploited for therapeutic benefit. .
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