5′-Triphosphate-RNA-independent activation of RIG-I via RNA aptamer with enhanced antiviral activity

Hwang, Sunyoung; Sun, Haiyan; Lee, Kwang-Hoon; Oh, Byung‐Ha; Jin, Yu; Kim, Byeang Hyean; Yoo, Joo‐Yeon

doi:10.1093/nar/gkr1098

Cited by 64 publications

(53 citation statements)

References 52 publications

(66 reference statements)

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“…Optimization of the prototypical VSV-derived WT 5=pppRNA (27,30) resulted in novel structures with enhanced antiviral activity compared to the short form of polyinosinic-polycytidylic acid [poly(I·C)], a well-known and -characterized TLR3 agonist, or the SELEX-selected RIG-I aptamers CL2 and CL9 (35). A representation of the predicted secondary structure of each of the agonists generated is included in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Primary sequence modification was sufficient to differentially trigger an innate response, although increased length of the sequence via additional UA pairings also enhanced the response. It has been reported that a poly(U) motif is required to produce an interferon response that establishes an antiviral state (35), and others observed enhanced activity with a poly(U) sequence, although they determined that it was not necessary to elicit a response (42)(43)(44). However, RIG-I-mediated immunity is not dependent on this specific moiety, as a number of RNA molecules trigger RIG-I without it.…”

Section: Discussionmentioning

confidence: 99%

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Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

Chiang

Beljanski

Yin

et al. 2015

J Virol

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The cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5=-triphosphate (5=ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5=ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5=pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5=pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replication in vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatment in vivo prolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5=pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses. IMPORTANCEThe development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral response in vitro and in vivo and was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5=pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.H uman-pathogenic RNA viral infections, including influenza, dengue, and chikungunya, pose significant threats to human health and safety. For this reason, the development of prophylactic and therapeutic antivirals to treat and limit spread of infection remains a growing unmet medical need. Currently, there are no therapeutics for the prevention or treatment of dengue or chikungunya infections, and approved antiviral compounds to treat influenza have si...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

Chiang

Beljanski

Yin

et al. 2015

J Virol

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“…One recent study reported that inhibition of viral infection by aptamers might be due to the aptamer-induced innate immune response (29). However, most studies suggest that inhibition of virus infection by aptamers targeting different viral proteins can be attributed to suppression of viral protein by the aptamers themselves (30)(31)(32)(33).…”

Section: Figmentioning

confidence: 99%

Inhibition of Hepatitis C Virus Production by Aptamers against the Core Protein

Shi

Gao

et al. 2014

J Virol

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bHepatitis C virus (HCV) core protein is essential for virus assembly. HCV core protein was expressed and purified. Aptamers against core protein were raised through the selective evolution of ligands by the exponential enrichment approach. Detection of HCV infection by core aptamers and the antiviral activities of aptamers were characterized. The mechanism of their anti-HCV activity was determined. The data showed that selected aptamers against core specifically recognize the recombinant core protein but also can detect serum samples from hepatitis C patients. Aptamers have no effect on HCV RNA replication in the infectious cell culture system. However, the aptamers inhibit the production of infectious virus particles. Beta interferon (IFN-␤) and interferon-stimulated genes (ISGs) are not induced in virally infected hepatocytes by aptamers. Domains I and II of core protein are involved in the inhibition of infectious virus production by the aptamers. V31A within core is the major resistance mutation identified. Further study shows that the aptamers disrupt the localization of core with lipid droplets and NS5A and perturb the association of core protein with viral RNA. The data suggest that aptamers against HCV core protein inhibit infectious virus production by disrupting the localization of core with lipid droplets and NS5A and preventing the association of core protein with viral RNA. The aptamers for core protein may be used to understand the mechanisms of virus assembly. Core-specific aptamers may hold promise for development as early diagnostic reagents and potential therapeutic agents for chronic hepatitis C.

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“…243 RIG-I antagonists may thus also be suited for treatment of viral infections and cancer. 244 A recent study has identified an RNA aptamer that binds to RIG-I, activates signaling, and blocks viral replication in infected host cells, demonstrating potential as an antiviral agent 245 and possibly also as an anti-cancer drug.…”

Section: Rna Helicases As Drug Targetsmentioning

confidence: 99%