@article{2e1d613a30754120adccea298c2d9c87,
title = "Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor",
abstract = "A chemical genetics approach was taken to identify inhibitors of NS1, a major influenza A virus virulence factor that inhibits host gene expression. A high-throughput screen of 200,000 synthetic compounds identified small molecules that reversed NS1-mediated inhibition of host gene expression. A counterscreen for suppression of influenza virus cytotoxicity identified naphthalimides that inhibited replication of influenza virus and vesicular stomatitis virus (VSV). The mechanism of action occurs through activation of REDD1 expression and concomitant inhibition of mammalian target of rapamycin complex 1 (mTORC1) via TSC1-TSC2 complex. The antiviral activity of naphthalimides was abolished in REDD1 -/- cells. Inhibition of REDD1 expression by viruses resulted in activation of the mTORC1 pathway. REDD1 -/- cells prematurely upregulated viral proteins via mTORC1 activation and were permissive to virus replication. In contrast, cells conditionally expressing high concentrations of REDD1 downregulated the amount of viral protein. Thus, REDD1 is a new host defense factor, and chemical activation of REDD1 expression represents a potent antiviral intervention strategy.",
author = "Mata, {Miguel A.} and Neal Satterly and Versteeg, {Gijs A.} and Doug Frantz and Shuguang Wei and Noelle Williams and Mirco Schmolke and Samuel Pe{\~n}a-Llopis and James Brugarolas and Forst, {Christian V.} and White, {Michael A.} and Adolfo Garc{\'i}a-Sastre and Roth, {Michael G.} and Fontoura, {Beatriz M A}",
note = "Funding Information: We thank R. Sakthivel (University of Texas Southwestern) for technical assistance with plaque assays and L. Melito and J. Naidoo (University of Texas Southwestern) for technical assistance with compound synthesis. We thank S. Rubin de Celis (University of Texas Southwestern) for providing REDD1 cells, D. Levy (New York University) for providing Stat1–⁄–cells and B. Levine (University of Texas Southwestern) for providing ATG5–⁄– cells and LC3 antibodies. This work was supported by US National Institutes of Health (NIH) grants R01GM07159 to B.M.A.F.; R01AI079110 and R01AI089539 to B.M.A.F. and M.G.R.; the Diane and Hal Brierley Distinguished Chair in Biomedical Research to M.G.R; National Center for Research Resources grant C06-RR15437; NIH grants R01AI046954, P01AI058113, U54AI057158 and U01AI074539; the Center for Research on Influenza Pathogenesis, the National Institute of Allergy and Infectious Diseases–funded Center of Excellence for Influenza Research and Surveillance (HHSN266200700010C to A.G.-S.); NIH grant R01CA129387 to J.B.; and support to M.A.M. from the NIH Diversity Supplement (R01GM06715908S1).",
year = "2011",
month = oct,
doi = "10.1038/nchembio.645",
language = "English (US)",
volume = "7",
pages = "712--719",
journal = "Nature chemical biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "10",
}