In this CETR program, 'Autophagy Modulators as Novel Broad-Spectrum Anti-infective Agents', we will discover, validate, and optimize novel broad-spectrum anti-infective agents. Our approach will be to enhance the anti-infective efficacy of a host pathway that is active against a wide range of NIAID priority pathogens. Autophagy and the function of autophagy-related genes (ATG genes) in resistance to infection represent such a pathway. Autophagy and ATG genes are central to immune defense against viruses, bacteria, and parasites including West Nile virus, chikungunya virus, norovirus, M. tuberculosis, S. aureus, T. gondii, L. monocytogenes, and S. typhimurium and therefore provide unique targets for the development of broad spectrum anti-infective agents. Autophagy is a cellular process in which cytoplasmic cargo, including pathogens and pathogen components, are captured within a double membrane-bound vesicle for delivery to the lysosome and degradation. ATG proteins can also play key roles in host defense via processes that do not require the autophagy pathway. In this CETR program we will develop small molecules that stimulate the activity of autophagy and/or ATG genes as broad-spectrum anti-infective agents. Our main deliverable will be semi-optimized lead compounds with protective effects in animals against a range of pathogens. We have already identified an autophagy-inducing peptide that protects mice against infection with diverse viruses, and have completed a high-density compound screen that has identified autophagy-inducing molecules that inhibit bacterial replication. We will develop these initial candidates, and will identify additional validated targets for further compound screens. Our team combines experts in the field including Drs. Skip Virgin, Beth Levine, Ramnik Xavier, and Stuart Schreiber, a group with an extensive history of collaboration and copublication. To accomplish our goals we will leverage the outstanding facilities and resources of the Broad Institute, the Massachusetts General Hospital, Washington University School of Medicine, and the University of Texas Southwestern Medical School. We will accomplish our goals through four Research Projects, an Administrative Core, and a Genetic and Pathway Analysis Core. Our Projects are: (1) Autophagy-Inducing Peptides and Target Identification for Treatment of Viruses (Levine);(2) Genes/Pathways for Autophagy dependent Inhibition of Bacterial Infection (Xavier);(3) Genes/Pathways for ATG Gene-dependent Inhibition of Virus and Parasite Infection (Virgin);and (4) Enhancing ATG-dependent Defense Against Pathogens with Therapeutic Lead Compounds (Schreiber). By focusing on autophagy and ATG genes, and using cutting edge technologies, our CETR team will optimize already existing therapeutic leads and provide a pipeline of novel targets for the development of a new class of broad-spectrum anti-infective medicines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109725-01
Application #
8642370
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Program Officer
Beanan, Maureen J
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$6,377,610
Indirect Cost
$541,146
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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