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    Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity.

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    Author
    Si, Longlong
    Bai, Haiqing
    Oh, Crystal Yuri
    Jiang, Amanda
    Hong, Fan
    Zhang, Tian
    Ye, Yongxin
    Jordan, Tristan X
    Logue, James
    McGrath, Marisa
    Belgur, Chaitra
    Calderon, Karina
    Nurani, Atiq
    Cao, Wuji
    Carlson, Kenneth E
    Prantil-Baun, Rachelle
    Gygi, Steven P
    Yang, Dong
    Jonsson, Colleen B
    tenOever, Benjamin R
    Frieman, Matthew
    Ingber, Donald E
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    Date
    2022-08-24
    Journal
    Molecular Therapy Nucleic Acids
    Publisher
    Cell Press
    Type
    Article
    
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    See at
    https://doi.org/10.1016/j.omtn.2022.08.031
    Abstract
    The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III). These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique sequence motif (sense strand: 5’-C, antisense strand: 3’-GGG) that mediates end-to-end dimer self-assembly. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with immunostimulant poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-NL63, and influenza A virus in cell lines, human Lung Chips that mimic organ-level lung pathophysiology, and a mouse SARS-CoV-2 infection model. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics.
    Rights/Terms
    © 2022 The Author(s).
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/19648
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.omtn.2022.08.031
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