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.

Public Health Relevance

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. .

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LR-M (J1))
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Washington University
Saint Louis
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