Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection
Che-Ming Jack Hu,1,2,* You-Ting Chen,3,* Zih-Syun Fang,1,3 Wei-Shan Chang,3 Hui-Wen Chen2,3 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 2Research Center for Nanotechnology and Infectious Diseases, Taipei, Taiwan; 3Department of Veterinary Medicine, National Taiwan University...
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doaj-acdc2ee6cfb74183b98bce98736abf482020-11-24T22:19:01ZengDove Medical PressInternational Journal of Nanomedicine1178-20132018-12-01Volume 138579859343059Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infectionHu CMJChen YTFang ZSChang WSChen HWChe-Ming Jack Hu,1,2,* You-Ting Chen,3,* Zih-Syun Fang,1,3 Wei-Shan Chang,3 Hui-Wen Chen2,3 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 2Research Center for Nanotechnology and Infectious Diseases, Taipei, Taiwan; 3Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan *These authors contributed equally to this work Background: Influenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application. Methods: In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs’ anti-influenza applicability. Results: Using PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater in vitro antiviral activity, improving the therapeutic index of diphyllin and bafilomycin by approximately 3 and 5-fold, respectively. In a mouse model of sublethal influenza challenge, treatment with diphyllin nanoparticles resulted in reduced body weight loss and viral titer in the lungs. In addition, following a lethal influenza viral challenge, diphyllin nanoparticle treatment conferred a survival advantage of 33%. Conclusions: These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza. Keywords: influenza virus, vacuolar ATPase inhibitor, diphyllin, bafilomycin, nanoparticleshttps://www.dovepress.com/antiviral-efficacy-of-nanoparticulate-vacuolar-atpase-inhibitors-again-peer-reviewed-article-IJNInfluenza virusVacuolar ATPase inhibitorDiphyllinBafilomycinNanoparticles |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hu CMJ Chen YT Fang ZS Chang WS Chen HW |
spellingShingle |
Hu CMJ Chen YT Fang ZS Chang WS Chen HW Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection International Journal of Nanomedicine Influenza virus Vacuolar ATPase inhibitor Diphyllin Bafilomycin Nanoparticles |
author_facet |
Hu CMJ Chen YT Fang ZS Chang WS Chen HW |
author_sort |
Hu CMJ |
title |
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_short |
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_full |
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_fullStr |
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_full_unstemmed |
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_sort |
antiviral efficacy of nanoparticulate vacuolar atpase inhibitors against influenza virus infection |
publisher |
Dove Medical Press |
series |
International Journal of Nanomedicine |
issn |
1178-2013 |
publishDate |
2018-12-01 |
description |
Che-Ming Jack Hu,1,2,* You-Ting Chen,3,* Zih-Syun Fang,1,3 Wei-Shan Chang,3 Hui-Wen Chen2,3 1Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; 2Research Center for Nanotechnology and Infectious Diseases, Taipei, Taiwan; 3Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan *These authors contributed equally to this work Background: Influenza virus infections are a major public health concern worldwide. Conventional treatments against the disease are designed to target viral proteins. However, the emergence of viral variants carrying drug-resistant mutations can outpace the development of pathogen-targeting antivirals. Diphyllin and bafilomycin are potent vacuolar ATPase (V-ATPase) inhibitors previously shown to have broad-spectrum antiviral activity. However, their poor water solubility and potential off-target effect limit their clinical application. Methods: In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs’ anti-influenza applicability. Results: Using PEG-PLGA diblock copolymers, sub-200 nm diphyllin and bafilomycin nanoparticles were prepared, with encapsulation efficiency of 42% and 100%, respectively. The drug-loaded nanoparticles have sustained drug release kinetics beyond 72 hours and facilitate intracellular drug delivery to two different influenza virus-permissive cell lines. As compared to free drugs, the nanoparticulate V-ATPase inhibitors exhibited lower cytotoxicity and greater in vitro antiviral activity, improving the therapeutic index of diphyllin and bafilomycin by approximately 3 and 5-fold, respectively. In a mouse model of sublethal influenza challenge, treatment with diphyllin nanoparticles resulted in reduced body weight loss and viral titer in the lungs. In addition, following a lethal influenza viral challenge, diphyllin nanoparticle treatment conferred a survival advantage of 33%. Conclusions: These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza. Keywords: influenza virus, vacuolar ATPase inhibitor, diphyllin, bafilomycin, nanoparticles |
topic |
Influenza virus Vacuolar ATPase inhibitor Diphyllin Bafilomycin Nanoparticles |
url |
https://www.dovepress.com/antiviral-efficacy-of-nanoparticulate-vacuolar-atpase-inhibitors-again-peer-reviewed-article-IJN |
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