Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature Chemical Biology (Impact Factor: 13). 09/2011; 7(10):712-9. DOI: 10.1038/nchembio.645
Source: PubMed


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.

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    • "Currently, there are several clinical trials on going using the neuraminidase inhibitors (e.g., Peramivir and Laninamivir) [11], [12]. In addition, inhibitors of RNA replication (e.g., Favipiravir) or NS1 viral protein has been under development as effective therapeutic candidates [2], [13]. However, it is quite challenging to develop drugs that are effective and safe on the systemic level, mainly due to the rapid alterations of influenza genome and complicated interactions between virus and host immunity [14], [15]. "
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    PLoS ONE 07/2013; 8(7):e68235. DOI:10.1371/journal.pone.0068235 · 3.23 Impact Factor
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    • "In a separate recent screen, host genes specifically important for influenza viral polymerase (RdRP) function were identified, which are also potential candidates for antiviral drug development [136]. A chemical biology screen of 200,000 synthetic compounds recently identified naphthalimides as an antiviral chemical class that activated a new host defense factor, REDD1, which in turn inhibited influenza NS1 and viral replication [137]. Thus, activation of REDD1, rather than inhibition, can be developed as a new anti-influenza regimen. "
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    BMC Medicine 09/2012; 10(1):104. DOI:10.1186/1741-7015-10-104 · 7.25 Impact Factor
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    • "Of interest in this class is RRAGD, a small G-protein that supports the amino-acid responsiveness of mTOR as a component of the “ragulator” [11]. Several reports have highlighted the importance of viral induction of mTOR for viral replication, but the mechanism is not fully elaborated [6], [12]. Given the participation of endosomes as a viral entry mechanism [13], it is tempting to speculate that RRAGD is a limiting host factor for viral corruption of mTOR regulation. "
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    PLoS ONE 08/2012; 7(8). DOI:10.1371/journal.pone.0039284 · 3.23 Impact Factor
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