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

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

  • J Biomed Sci. 2026 May 27;33(1):55. doi: 10.1186/s12929-026-01262-x.
Yeong Jun Kim # 1,  Moumita Das # 2,  JunYoung Song # 1,  Shreyasi Das 2,  Han-Jun Kim 3,  Jeong-Ki Kim 3,  Ki-Young Lee 4,  Kyeong Kyu Kim 5 6,  Hye-Ra Lee 7 8
Affiliations

Affiliations

  • 1 Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, 2511 Sejong-Ro, Sejong, 30019, Republic of Korea.
  • 2 Department of Precision Medicine, Graduate School of Biomedical Science (GSBMS), Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
  • 3 College of Pharmacy, Korea University, Sejong, 30019, Republic of Korea.
  • 4 Department of Pharmacy, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
  • 5 Department of Precision Medicine, Graduate School of Biomedical Science (GSBMS), Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea. [email protected].
  • 6 Institute for Antimicrobial Resistance and Therapeutics, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea. [email protected].
  • 7 Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, 2511 Sejong-Ro, Sejong, 30019, Republic of Korea. [email protected].
  • 8 Department of Lab Medicine, College of Medicine, Korea University, Seoul, 136-701, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 42204560 DOI: 10.1186/s12929-026-01262-x
Abstract

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.

Keywords

Antivirals; BRACO-19; Dengue virus; Flaviviruses; G-quadruplex.

Figures
Products