Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity.
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Author
Si, LonglongBai, 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
Date
2022-08-24Journal
Molecular Therapy Nucleic AcidsPublisher
Cell PressType
Article
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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/10713/19648ae974a485f413a2113503eed53cd6c53
10.1016/j.omtn.2022.08.031
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