Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses

Tina M. Sali, Kara M. Pryke, Jinu Abraham, Andrew Liu, Iris Archer, Rebecca Broeckel, Julia Staverosky, Jessica L. Smith, Ahmed Al-Shammari, Lisi Amsler, Kayla Sheridan, Aaron Nilsen, Daniel Streblow, Victor De Filippis

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. In light of this we sought to identify small molecules capable of activating the type I interferon (IFN) response by way of the transcription factor IFN regulatory factor 3 (IRF3). A high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (referred to herein as G10), which was found to trigger IRF3/IFN-associated transcription in human fibroblasts. Further examination of the cellular response to this molecule revealed expression of multiple IRF3-dependent antiviral effector genes as well as type I and III IFN subtypes. This led to the establishment of a cellular state that prevented replication of emerging Alphavirus species including Chikungunya virus, Venezuelan Equine Encephalitis virus, and Sindbis virus. To define cellular proteins essential to elicitation of the antiviral activity by the compound we employed a reverse genetics approach that utilized genome editing via CRISPR/Cas9 technology. This allowed the identification of IRF3, the IRF3-activating adaptor molecule STING, and the IFN-associated transcription factor STAT1 as required for observed gene induction and antiviral effects. Biochemical analysis indicates that G10 does not bind to STING directly, however. Thus the compound may represent the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes. In vivo stimulation of STING-dependent activity by an unrelated small molecule in a mouse model of Chikungunya virus infection blocked viremia demonstrating that pharmacologic activation of this signaling pathway may represent a feasible strategy for combating emerging Alphaviruses.

Original languageEnglish (US)
Article numbere1005324
JournalPLoS Pathogens
Volume11
Issue number12
DOIs
StatePublished - 2015

Fingerprint

Interferon Regulatory Factor-3
Alphavirus
Antiviral Agents
Interferon Type I
Interferons
Clustered Regularly Interspaced Short Palindromic Repeats
Venezuelan Equine Encephalitis Viruses
Chikungunya virus
STAT1 Transcription Factor
Sindbis Virus
Reverse Genetics
Viremia
Virus Replication
Genes
Immunity
Transcription Factors
Fibroblasts
Technology
Phenotype
Proteins

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Sali, T. M., Pryke, K. M., Abraham, J., Liu, A., Archer, I., Broeckel, R., ... De Filippis, V. (2015). Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathogens, 11(12), [e1005324]. https://doi.org/10.1371/journal.ppat.1005324

Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. / Sali, Tina M.; Pryke, Kara M.; Abraham, Jinu; Liu, Andrew; Archer, Iris; Broeckel, Rebecca; Staverosky, Julia; Smith, Jessica L.; Al-Shammari, Ahmed; Amsler, Lisi; Sheridan, Kayla; Nilsen, Aaron; Streblow, Daniel; De Filippis, Victor.

In: PLoS Pathogens, Vol. 11, No. 12, e1005324, 2015.

Research output: Contribution to journalArticle

Sali, TM, Pryke, KM, Abraham, J, Liu, A, Archer, I, Broeckel, R, Staverosky, J, Smith, JL, Al-Shammari, A, Amsler, L, Sheridan, K, Nilsen, A, Streblow, D & De Filippis, V 2015, 'Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses', PLoS Pathogens, vol. 11, no. 12, e1005324. https://doi.org/10.1371/journal.ppat.1005324
Sali, Tina M. ; Pryke, Kara M. ; Abraham, Jinu ; Liu, Andrew ; Archer, Iris ; Broeckel, Rebecca ; Staverosky, Julia ; Smith, Jessica L. ; Al-Shammari, Ahmed ; Amsler, Lisi ; Sheridan, Kayla ; Nilsen, Aaron ; Streblow, Daniel ; De Filippis, Victor. / Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. In: PLoS Pathogens. 2015 ; Vol. 11, No. 12.
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