A minimal RNA ligand for potent RIG-I activation in living mice

Linehan, Melissa; Dickey, Thayne H.; Molinari, Emanuela; Fitzgerald, Megan; Potapova, Olga; Iwasaki, Akiko; Pyle, Anna Marie

doi:10.1126/sciadv.1701854

Cited by 91 publications

(155 citation statements)

References 71 publications

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“…The retinoic acid‐inducible gene‐I (RIG‐I)‐like receptors sense intracellular RNA. These include the prototypical RIG‐I, which is activated by ssRNA as short as 10 nt harbouring a di‐ or tri‐phosphorylated 5′ end . MDA5 is activated by large RNA molecules, while LGP2 recognises RNA as short as 12 nt irrespective of phosphorylation or hydroxylation at the 5′ end.…”

Section: Challenges and Strategies In Targeting Multifunctional Host mentioning

confidence: 99%

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Heaton

2019

Clin & Trans Imm

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Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse‐transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means to extract maximum utility from their informationally limited genomes that, correspondingly, may be leveraged for effective host‐oriented therapies. Host‐oriented approaches are becoming increasingly feasible because of increased availability of bioactive compounds and recent advances in immunotherapy and precision medicine, particularly genome editing, targeted delivery methods and RNAi. In turn, one driving force behind these innovations is the increasingly detailed understanding of evolutionarily diverse host–virus interactions, which is the key concern of an emerging field, neo‐virology. This review examines biotechnological solutions to disease and other sustainability issues of our time that leverage the properties of RNA and DNA viruses as developed through co‐evolution with their hosts.

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Section: Challenges and Strategies In Targeting Multifunctional Host mentioning

confidence: 99%

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Heaton

2019

Clin & Trans Imm

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“…Thus, we will only highlight the recent advances and concepts relevant to the design of selective and potent RIG-I and MDA5 agonists. Using in vitro transcribed (ivt) viral RNA analogs, it was determined that the consensus minimum RNA size required for RIG-I recognition and signal transduction is as short as 10 bp, but the maximum size over which binding to RIG-I is suppressed remains unknown [6][7][8][9]. By contrast, it is generally accepted that MDA5 senses high molecular weight (HMW) RNA species [7,10].…”

Section: Rig-i and Mda5 Ligand-binding Specificities: What Do We Know?mentioning

confidence: 99%

“…In addition, CBS-13-BPS triggered significant tumor regression in a murine pancreatic tumor model, indicating potential as a cancer immunotherapeutic [62]. A third type of RIG-I agonist, in the form of 5 0 ppp RNA harboring a stem-loop (SLR10 and SLR14), was recently found to induce greater IFN-I response compared to poly(I:C) in vivo; however, it remains to be tested in prophylactic or therapeutic contexts [9].…”

Section: Targeting Rlrs For Therapeutic and Prophylactic Strategiesmentioning

confidence: 99%

“…The poly(I:C) analogs, rb-dsRNA and NAB2, concomitantly activate TLR3, which is associated with a strong inflammatory response [73]. Complex formulations, such as the JetPEI transfection reagent, have been successfully used in vivo in mice for intracellular delivery of RIG-I ligands to bypass TLR3 activation [9,30,62] (Table 1). This approach would be worth testing with MDA5 ligands in preclinical studies.…”

Section: Targeting Rlrs For Therapeutic and Prophylactic Strategiesmentioning

confidence: 99%

“…Both IFN-I and -III transcriptional signatures are induced in vitro by VSV-derived 5 0 ppp-RNA RIG-I ligands ( Table 1), but the balance between the two responses remains to be fully evaluated in vivo [30,60]. SLR10 and 14 ligands (Table 1) selectively induce high IFN-I gene expression associated with a weak type IFN-III response, a balance that is opposite to that triggered by poly(I:C) [9]. Although data using poly(I:C), which is recognized by MDA5, suggest a more favorable IFN balance for antiviral applications, such evidence using MDA5-specific ligands is not yet available.…”

Section: Targeting Rlrs For Therapeutic and Prophylactic Strategiesmentioning

confidence: 99%

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Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome

Kasumba

Grandvaux

2019

Trends in Pharmacological Sciences

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publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.Highlights RNA-based agonists targeting RIG-I or MDA5 are at the center of an ongoing hunt for novel pan-antivirals, vaccine adjuvants, and antitumor strategies.

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Structure‐guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG‐I

Yong

Zheng

et al. 2019

FEBS Letters

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The cytoplasmic immune sensor RIG‐I detects viral RNA and initiates an antiviral immune response upon activation. It has become a potential target for vaccination and immunotherapies. To develop the smallest but potent immunomodulatory RNA (immRNAs) species, we performed structure‐guided RNA design and used biochemical, structural, and cell‐based methods to select and characterize the immRNAs. We demonstrated that inserting guanosine at position 9 to the 10mer RNA hairpin (3p10LG9) activates RIG‐I more robustly than the parental RNA. 3p10LG9 interacts strongly with the RIG‐I helicase‐CTD RNA sensing module and disrupts the auto‐inhibitory interaction between the HEL2i and CARDs domains. We further showed that 3p10LA9 has a stronger cellular activity than 3p10LG9. Collectively, purine insertion at position 9 of the immRNA species triggered more robust activation of RIG‐1.

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A minimal RNA ligand for potent RIG-I activation in living mice

Abstract: Short stem-loop RNAs activate RIG-I in mice, activating the innate immune system via specific patterns of gene expression.

Cited by 91 publications

References 71 publications

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Harnessing host–virus evolution in antiviral therapy and immunotherapy

Therapeutic Targeting of RIG-I and MDA5 Might Not Lead to the Same Rome

Structure‐guided design of immunomodulatory RNAs specifically targeting the cytoplasmic viral RNA sensor RIG‐I

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