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Inst. Oswaldo Cruz"],"abstract":"<jats:p>BACKGROUND  Zika virus (ZIKV) was first identified in the Americas in 2015, with Brazil experiencing a major epidemic marked by teratogenic effects during early pregnancy. Ex vivo studies of microglia from fatal ZIKV-induced microcephaly cases revealed elevated levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Direct-acting antivirals (DAAs) have been proposed as potential ZIKV treatments.  OBJECTIVES  This study aimed to investigate the effects of two DAAs, simeprevir and sofosbuvir, on iNOS expression and NO production during in vitro ZIKV infection.  METHODS  Molecular docking analyses were performed to assess the interaction between DAAs and the iNOS enzyme. ZIKV-infected Vero CCL-81 cells were treated with simeprevir or sofosbuvir (10 \u00b5mol\/L), and iNOS expression, NO production, and cytotoxicity were evaluated.  FINDINGS  Both DAAs demonstrated strong binding affinity to the iNOS active site. Compared with the untreated infected controls, treatment with simeprevir and sofosbuvir significantly upregulated iNOS expression and increased NO production by approximately 60%. No cytotoxic effects were observed under the experimental conditions.  MAIN CONCLUSIONS  Simeprevir and sofosbuvir not only exhibit antiviral properties but also may enhance the host antiviral response via modulation of the NO pathway, suggesting a dual mechanism of action against ZIKV.<\/jats:p>","DOI":"10.1590\/0074-02760250315","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:54:04Z","timestamp":1790592844000},"source":"Crossref","is-referenced-by-count":0,"title":["Enhancement of simeprevir and sofosbuvir anti-ZIKV activity by iNOS-derived NO in vitro"],"prefix":"10.1590","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-2869","authenticated-orcid":false,"given":"R\u00f4mulo Jos\u00e9","family":"Soares-Bezerra","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen dos Santos","family":"Charret","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Marcos Beserra Rocha","family":"da Silva","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana Miranda","family":"Mamprim","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas de Souza","family":"Leite","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard de Almeida","family":"Lima","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela del Ros\u00e1rio Flores","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre dos Santos","family":"da Silva","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natiele Carla da Silva","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]},{"name":"Universidade Federal do Rio de Janeiro","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Alves","family":"Pinto","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz","place":["Rio de Janeiro, RJ, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"530","published-online":{"date-parts":[[2026]]},"reference":[{"issue":"3","key":"ref1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrmicro.2017.170","article-title":"Rewiring cellular networks by members of the Flaviviridae family","volume":"16","author":"Neufeldt CJ","year":"2018","journal-title":"Nat Rev Microbiol"},{"issue":"4","key":"ref2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00705-006-0903-z","article-title":"Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses","volume":"152","author":"Kuno G","year":"2007","journal-title":"Arch Virol"},{"issue":"9","key":"ref3","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/j.celrep.2017.02.014","article-title":"Ultrastructural characterization of Zika virus replication factories","volume":"18","author":"Cortese M","year":"2017","journal-title":"Cell Rep"},{"issue":"3","key":"ref4","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s12275-017-7063-6","article-title":"Zika virus: an emerging flavivirus","volume":"55","author":"Yun SI","year":"2017","journal-title":"J Microbiol"},{"issue":"7","key":"ref5","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3201\/eid2207.151990","article-title":"A literature review of Zika virus","volume":"22","author":"Plourde AR","year":"2016","journal-title":"Emerg Infect Dis"},{"issue":"5","key":"ref6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0035-9203(52)90043-6","article-title":"Zika virus (II). 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