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Background <p>Given the increasing global incidence of dengue virus (DENV) infections and the lack of approved antiviral therapies, developing a new antiviral strategy against DENV is urgently required. However, despite considerable efforts to develop protein-targeted antivirals, clinical translation has largely failed, highlighting the need for alternative, non-protein targets.</p> Methods <p>Here, we investigated a novel therapeutic approach that targets RNA G-quadruplexes (G4s), highly conserved secondary structures across viral strains, including all serotypes. Bioinformatic predictions and biophysical analyses identified conserved G4-forming sequences within the DENV genome.</p> Results <p>Among the tested representative G4-binding ligands, BRACO-19 showed the highest stabilizing effect on G4 structures, particularly at the G4-3 region corresponding to the NS3 gene with high binding affinity. Functionally, BRACO-19 treatment significantly reduced viral translation resulting in strong antiviral effects in a mouse model of DENV infection. Consistently, recombinant DENV carrying a G4-3-disrupting mutation showed enhanced viral gene expression and attenuated sensitivity to BRACO-19. These findings establish DENV RNA G4 as a druggable structural element and position BRACO-19 as a promising lead compound for dengue therapeutics. Furthermore, we also demonstrated that BRACO-19 exhibits broad-spectrum activity against all DENV serotypes. This RNA structure-based approach offers an alternative to protein-targeted therapeutics, helping to mitigate mutational escape and serotype variability in dengue virus.</p> Conclusion <p>Collectively, our study highlights a novel therapeutic strategy that directly targets conserved RNA secondary structures, paving the way for the development of broad-spectrum antivirals against flaviviruses by targeting a non-canonical nucleic acid structure.</p>

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Targeting a genomic RNA G-quadruplex of dengue virus with small molecules as an alternative to protein-targeted therapeutics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Yeong Jun Kim,
  • Moumita Das,
  • JunYoung Song,
  • Shreyasi Das,
  • Han-Jun Kim,
  • Jeong-Ki Kim,
  • Ki-Young Lee,
  • Kyeong Kyu Kim,
  • Hye-Ra Lee

摘要

Background

Given the increasing global incidence of dengue virus (DENV) infections and the lack of approved antiviral therapies, developing a new antiviral strategy against DENV is urgently required. However, despite considerable efforts to develop protein-targeted antivirals, clinical translation has largely failed, highlighting the need for alternative, non-protein targets.

Methods

Here, we investigated a novel therapeutic approach that targets RNA G-quadruplexes (G4s), highly conserved secondary structures across viral strains, including all serotypes. Bioinformatic predictions and biophysical analyses identified conserved G4-forming sequences within the DENV genome.

Results

Among the tested representative G4-binding ligands, BRACO-19 showed the highest stabilizing effect on G4 structures, particularly at the G4-3 region corresponding to the NS3 gene with high binding affinity. Functionally, BRACO-19 treatment significantly reduced viral translation resulting in strong antiviral effects in a mouse model of DENV infection. Consistently, recombinant DENV carrying a G4-3-disrupting mutation showed enhanced viral gene expression and attenuated sensitivity to BRACO-19. These findings establish DENV RNA G4 as a druggable structural element and position BRACO-19 as a promising lead compound for dengue therapeutics. Furthermore, we also demonstrated that BRACO-19 exhibits broad-spectrum activity against all DENV serotypes. This RNA structure-based approach offers an alternative to protein-targeted therapeutics, helping to mitigate mutational escape and serotype variability in dengue virus.

Conclusion

Collectively, our study highlights a novel therapeutic strategy that directly targets conserved RNA secondary structures, paving the way for the development of broad-spectrum antivirals against flaviviruses by targeting a non-canonical nucleic acid structure.