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However, despite considerable efforts to develop protein-targeted antivirals, clinical translation has largely failed, highlighting the need for alternative, non-protein targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01262-x","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:14:19Z","timestamp":1779912859000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting a genomic RNA G-quadruplex of dengue virus with small molecules as an alternative to protein-targeted therapeutics"],"prefix":"10.1186","volume":"33","author":[{"given":"Yeong Jun","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moumita","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JunYoung","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreyasi","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Jun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Ki","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki-Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyeong Kyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye-Ra","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"issue":"2","key":"1262_CR1","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3390\/v13020196","volume":"13","author":"S Artusi","year":"2021","unstructured":"Artusi S, Ruggiero E, Nadai M, Tosoni B, Perrone R, Ferino A, Zanin I, Xodo L, Flamand L, Richter SN. 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