{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:36:00Z","timestamp":1792154160373,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T00:00:00Z","timestamp":1726272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81773631"],"award-info":[{"award-number":["81773631"]}]},{"name":"National Natural Science Foundation of China","award":["2018ZX09711003"],"award-info":[{"award-number":["2018ZX09711003"]}]},{"name":"National Science and Technology Major Projects \u201cMajor New Drugs Innovation and Development\u201d","award":["81773631"],"award-info":[{"award-number":["81773631"]}]},{"name":"National Science and Technology Major Projects \u201cMajor New Drugs Innovation and Development\u201d","award":["2018ZX09711003"],"award-info":[{"award-number":["2018ZX09711003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.<\/jats:p>","DOI":"10.3390\/v16091467","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T04:14:07Z","timestamp":1726460047000},"page":"1467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Synergistic Effect of Baloxavir and Neuraminidase Inhibitors against Influenza Viruses In Vitro"],"prefix":"10.3390","volume":"16","author":[{"given":"Xiaojia","family":"Guo","sequence":"first","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Beijing Sunho Pharmaceutical Co., Ltd., Beijing 102600, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0536-620X","authenticated-orcid":false,"given":"Wu","family":"Zhong","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza. Nature reviews","volume":"4","author":"Krammer","year":"2018","journal-title":"Dis. Primers"},{"key":"ref_2","first-page":"2","article-title":"A Narrative Review of Influenza: A Seasonal and Pandemic Disease","volume":"42","author":"Moghadami","year":"2017","journal-title":"Iran. J. Med. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"A6","DOI":"10.1016\/j.vaccine.2020.09.048","article-title":"The disease burden of influenza beyond respiratory illness","volume":"39","author":"Macias","year":"2021","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1007\/s10096-020-03840-9","article-title":"Influenza and antiviral resistance: An overview","volume":"39","author":"Lampejo","year":"2020","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.antiviral.2012.05.004","article-title":"Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice","volume":"95","author":"Simeonova","year":"2012","journal-title":"Antivir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5220","DOI":"10.1128\/AAC.03313-14","article-title":"Characterization of drug-resistant influenza virus A(H1N1) and A(H3N2) variants selected in vitro with laninamivir","volume":"58","author":"Samson","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Batool, S., Chokkakula, S., and Song, M.S. (2023). Influenza Treatment: Limitations of Antiviral Therapy and Advantages of Drug Combination Therapy. Microorganisms, 11.","DOI":"10.3390\/microorganisms11010183"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00301-20","DOI":"10.1128\/AAC.00301-20","article-title":"Laninamivir-Interferon Lambda 1 Combination Treatment Promotes Resistance by Influenza A Virus More Rapidly than Laninamivir Alone","volume":"64","author":"Adams","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.virol.2007.12.029","article-title":"Injectable peramivir mitigates disease and promotes survival in ferrets and mice infected with the highly virulent influenza virus, A\/Vietnam\/1203\/04 (H5N1)","volume":"374","author":"Yun","year":"2008","journal-title":"Virology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.antiviral.2018.10.008","article-title":"In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit","volume":"160","author":"Noshi","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1056\/NEJMoa1915341","article-title":"Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts","volume":"383","author":"Ikematsu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1007\/s40265-020-01350-8","article-title":"Baloxavir Marboxil: A Review in Acute Uncomplicated Influenza","volume":"80","author":"Shirley","year":"2020","journal-title":"Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Omoto, S., Speranzini, V., Hashimoto, T., Noshi, T., Yamaguchi, H., Kawai, M., Kawaguchi, K., Uehara, T., Shishido, T., and Naito, A. (2018). Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-27890-4"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5419","DOI":"10.1128\/JVI.03513-14","article-title":"Neuraminidase Mutations Conferring Resistance to Oseltamivir in Influenza A(H7N9) Viruses","volume":"89","author":"Marjuki","year":"2015","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gillman, A., Muradrasoli, S., S\u00f6derstr\u00f6m, H., Nordh, J., Br\u00f6jer, C., Lindberg, R.H., Latorre-Margalef, N., Waldenstr\u00f6m, J., Olsen, B., and J\u00e4rhult, J.D. (2013). Resistance mutation R292K is induced in influenza A(H6N2) virus by exposure of infected mallards to low levels of oseltamivir. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071230"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104886","DOI":"10.1016\/j.antiviral.2020.104886","article-title":"Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses","volume":"182","author":"Bialy","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4855","DOI":"10.1128\/AAC.48.12.4855-4863.2004","article-title":"Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells","volume":"48","author":"Govorkova","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Park, S., Kim, J.I., Lee, I., Lee, S., Hwang, M.W., Bae, J.Y., Heo, J., Kim, D., Jang, S.I., and Kim, H. (2014). Combination effects of peramivir and favipiravir against oseltamivir-resistant 2009 pandemic influenza A(H1N1) infection in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0101325"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Nguyen, J.T., Hoopes, J.D., Le, M.H., Smee, D.F., Patick, A.K., Faix, D.J., Blair, P.J., de Jong, M.D., Prichard, M.N., and Went, G.T. (2010). Triple combination of amantadine, ribavirin, and oseltamivir is highly active and synergistic against drug resistant influenza virus strains in vitro. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009332"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.antiviral.2010.09.020","article-title":"Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model","volume":"88","author":"Bantia","year":"2010","journal-title":"Antivir. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Checkmahomed, L., Padey, B., Pizzorno, A., Terrier, O., Rosa-Calatrava, M., Abed, Y., Baz, M., and Boivin, G. (2020). In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses. Viruses, 12.","DOI":"10.3390\/v12101139"},{"key":"ref_22","first-page":"215","article-title":"Evaluation of the efficacy and safety of a statin\/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB\/c mice","volume":"38","author":"Liu","year":"2009","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104906","DOI":"10.1016\/j.antiviral.2020.104906","article-title":"Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods","volume":"182","author":"Patel","year":"2020","journal-title":"Antivir. Res."},{"key":"ref_24","first-page":"367","article-title":"Replicative Fitness of Seasonal Influenza a Viruses with Decreased Susceptibility to Baloxavir","volume":"221","author":"Chesnokov","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1093\/jac\/dkad145","article-title":"Efficacy of favipiravir against influenza virus resistant to both baloxavir and neuraminidase inhibitors","volume":"78","author":"Kiso","year":"2023","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Mtambo, S.E., Ugbaja, S.C., and Kumalo, H.M. (2022). Impact of the R292K Mutation on Influenza A (H7N9) Virus Resistance towards Peramivir: A Molecular Dynamics Perspective. Molecules, 27.","DOI":"10.3390\/molecules27051645"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e78","DOI":"10.1038\/emi.2014.80","article-title":"Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) with R292K substitution","volume":"3","author":"Zhang","year":"2014","journal-title":"Emerg. Microbes Infect."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1128\/AAC.01579-07","article-title":"Oseltamivir-ribavirin combination therapy for highly pathogenic H5N1 influenza virus infection in mice","volume":"52","author":"Ilyushina","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Hoopes, J.D., Driebe, E.M., Kelley, E., Engelthaler, D.M., Keim, P.S., Perelson, A.S., Rong, L., Went, G.T., and Nguyen, J.T. (2011). Triple combination antiviral drug (TCAD) composed of amantadine, oseltamivir, and ribavirin impedes the selection of drug-resistant influenza A virus. 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