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. .
|Galluzzi, Lorenzo; Bravo-San Pedro, José Manuel; Levine, Beth et al. (2017) Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16:487-511|
|Rocchi, Altea; Yamamoto, Soh; Ting, Tabitha et al. (2017) A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLoS Genet 13:e1006962|
|Baldridge, Megan T; Lee, Sanghyun; Brown, Judy J et al. (2017) Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus. J Virol 91:|
|Goodwin, Jonathan M; Dowdle, William E; DeJesus, Rowena et al. (2017) Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9. Cell Rep 20:2341-2356|
|Lassen, K G; Xavier, R J (2017) Genetic control of autophagy underlies pathogenesis of inflammatory bowel disease. Mucosal Immunol 10:589-597|
|Franco, Luis H; Nair, Vidhya R; Scharn, Caitlyn R et al. (2017) The Ubiquitin Ligase Smurf1 Functions in Selective Autophagy of Mycobacterium tuberculosis and Anti-tuberculous Host Defense. Cell Host Microbe 22:421-423|
|Li, Yue; Zhao, Yuting; Su, Minfei et al. (2017) Structural insights into the interaction of the conserved mammalian proteins GAPR-1 and Beclin 1, a key autophagy protein. Acta Crystallogr D Struct Biol 73:775-792|
|Köster, Stefan; Upadhyay, Sandeep; Chandra, Pallavi et al. (2017) Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA. Proc Natl Acad Sci U S A 114:E8711-E8720|
|Bartolomeo, Rosa; Cinque, Laura; De Leonibus, Chiara et al. (2017) mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy. J Clin Invest 127:3717-3729|
|Murano, Tatsuro; Najibi, Mehran; Paulus, Geraldine L C et al. (2017) Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo. Sci Rep 7:13938|
Showing the most recent 10 out of 80 publications