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Although the dengue virus (DENV) replication cycle primarily takes place in the cytoplasm, the capsid protein and non-structural protein 5 (NS5) are imported into the nucleus through a nuclear localization sequence-dependent mechanism. However, given its small molecular weight (14\u2009kDa), the DENV capsid protein may also enter the nucleus via passive diffusion. While some drugs primarily inhibit active nuclear transport, few are known to block passive diffusion. Notably, biguanides have been associated with inhibitory effects on passive nuclear transport. Since biguanides such as metformin (MET) exhibit anti-DENV properties, we investigated the effects of MET on the nuclear transport of DENV proteins. Our results suggest that MET induces changes in the nuclear membrane of Huh-7 cells and reduces capsid nuclear localization without affecting NS5 nuclear import. Furthermore, MET treatment did not alter capsid nuclear import in BHK-21 cells. Additionally, mimicking MET\u2019s effects using a non-hydrolyzable ATP analogue increased capsid cytoplasmic retention and decreased DENV-2 replication. Finally, the inhibition of the classical active nuclear transport pathway did not block capsid nuclear transport, suggesting that DENV-2 capsid enters the nucleus in Huh-7 and Vero cells independently of this pathway.<\/jats:p>","DOI":"10.1099\/jgv.0.002089","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T17:42:40Z","timestamp":1742492560000},"source":"Crossref","is-referenced-by-count":5,"title":["Cytoplasmic retention of dengue virus capsid protein by metformin impairing nuclear transport"],"prefix":"10.1099","volume":"106","author":[{"given":"Ian Carlos","family":"Puello-Nakayama","sequence":"first","affiliation":[{"name":"Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Hernandez-Castillo","sequence":"additional","affiliation":[{"name":"Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Manuel","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City 07360, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Talam\u00e1s-Lara","sequence":"additional","affiliation":[{"name":"Unidad de Microscop\u00eda Electr\u00f3nica, Laboratorios Nacionales de Servicios Experimentales (LaNSE), Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional (CINVESTAV-IPN), Av. 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