{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:56:54Z","timestamp":1787029014080,"version":"build-2736575974"},"reference-count":90,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FUNDACI\u00d3N IMSS, A.C.","award":["R-2024-785-073"],"award-info":[{"award-number":["R-2024-785-073"]}]},{"name":"SECIHTI","award":["CBF-2025-I-1331"],"award-info":[{"award-number":["CBF-2025-I-1331"]}]},{"name":"SECIHTI","award":["CVU 780737"],"award-info":[{"award-number":["CVU 780737"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>SARS-CoV-2 continues to evolve into immune-evasive variants, and although vaccination remains the cornerstone of prevention, the search for antiviral molecules targeting conserved viral enzymes remains essential. The RNA-dependent RNA polymerase (NSP12) is a central component of coronavirus replication, and natural polyphenols have been recurrently proposed as modulators of viral polymerases. Among these compounds, Fisetin has been reported to interact with multiple viral and cellular pathways, yet its direct antiviral activity against SARS-CoV-2 remained largely unexplored. Here, we first analyzed the interaction of Fisetin with the catalytic and NiRAN domains of NSP12 using molecular docking and molecular dynamics simulations, revealing stable and energetically favorable binding throughout a 100 ns simulation. Previous biochemical reports have shown that Fisetin inhibits the recombinant SARS-CoV-2 RdRp, supporting its potential to engage the polymerase. We then evaluated its antiviral activity in human A549 lung epithelial cells infected with the Omicron JN.1 variant. We observed a clear dose-dependent reduction in viral infection, achieving up to 91.9% inhibition at 3 \u03bcM while maintaining acceptable cell viability. In addition, Fisetin displayed a selectivity index superior to that of Lopinavir, the positive antiviral control used in this study. Altogether, our findings demonstrate that Fisetin possesses reproducible antiviral activity in a physiologically relevant human lung model and support its role as a natural scaffold for the rational development of polymerase-targeting antivirals against emerging SARS-CoV-2 variants.<\/jats:p>","DOI":"10.3390\/microorganisms13122809","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:20:57Z","timestamp":1765369257000},"page":"2809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Fisetin as an Antiviral Agent Targeting the RNA-Dependent RNA Polymerase of SARS-CoV-2: Computational Prediction and In Vitro Experimental Validation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1930-2685","authenticated-orcid":false,"given":"Ximena","family":"Hern\u00e1ndez-Rodr\u00edguez","sequence":"first","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flor Itzel","family":"Lira-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2379-8591","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Reyes-Ru\u00edz","sequence":"additional","affiliation":[{"name":"Unidad M\u00e9dica de Alta Especialidad, Hospital de Especialidades No. 14, Centro M\u00e9dico Nacional \u201cAdolfo Ruiz Cortines\u201d, Instituto Mexicano del Seguro Social (IMSS), Veracruz 91897, Mexico"},{"name":"Facultad de Medicina, Regi\u00f3n Veracruz, Universidad Veracruzana (UV), Veracruz 91700, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8280-9812","authenticated-orcid":false,"given":"Juan Fidel","family":"Osuna-Ramos","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Autonomous University of Sinaloa, Culiac\u00e1n 80246, Mexico"},{"name":"Laboratorio de Virolog\u00eda y Dise\u00f1o de Antivirales, Facultad de Medicina, Universidad Aut\u00f3noma de Sinaloa (UAS), Culiac\u00e1n 80246, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Noe","family":"Farf\u00e1n-Morales","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Naturales, Universidad Aut\u00f3noma Metropolitana (UAM), Unidad Cuajimalpa, Mexico City 05348, Mexico"},{"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":"Daniela Nahomi","family":"Calder\u00f3n-Sandate","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio Enrique","family":"Casta\u00f1eda-Delgado","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5726-5953","authenticated-orcid":false,"given":"Mois\u00e9s","family":"Le\u00f3n-Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Perinatal y Dise\u00f1o Molecular de Ant\u00edgenos y Biomarcadores, Departamento de Inmunobioquimica, Instituto Nacional de Perinatolog\u00eda \u201cIsidro Espinosa de los Reyes\u201d, Mexico City 11000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6785-2035","authenticated-orcid":false,"given":"Rosa Mar\u00eda del","family":"\u00c1ngel","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1521-1519","authenticated-orcid":false,"given":"Bruno","family":"Rivas-Santiago","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u00fal","family":"Noriega","sequence":"additional","affiliation":[{"name":"Unidad Acad\u00e9mica de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Zacatecas, Zacatecas 98160, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8050-4587","authenticated-orcid":false,"given":"David Mauricio","family":"Ca\u00f1edo-Figueroa","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"},{"name":"Faculty of Medicine, Autonomous University of Sinaloa, Culiac\u00e1n 80246, Mexico"},{"name":"Laboratorio de Virolog\u00eda y Dise\u00f1o de Antivirales, Facultad de Medicina, Universidad Aut\u00f3noma de Sinaloa (UAS), Culiac\u00e1n 80246, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0420-4268","authenticated-orcid":false,"given":"Sarita","family":"Monta\u00f1o","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Bioinformatics, Facultad de Ciencias Qu\u00edmico-Biol\u00f3gicas of Universidad Aut\u00f3noma de Sinaloa, Culiac\u00e1n 80246, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4853-3063","authenticated-orcid":false,"given":"Alan Orlando","family":"Santos-Mena","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina","family":"Garc\u00eda-Herrera","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1415-6260","authenticated-orcid":false,"given":"Luis Adri\u00e1n","family":"De Jes\u00fas-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Laboratorio de Virolog\u00eda Molecular, Unidad de Investigaci\u00f3n Biom\u00e9dica de Zacatecas, Instituto Mexicano del Seguro Social, Zacatecas 98000, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","unstructured":"(2021, April 23). 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