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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Autores principales:	Hu CMJ, Chen YT, Fang ZS, Chang WS, Chen HW
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	Influenza virus Vacuolar ATPase inhibitor Diphyllin Bafilomycin Nanoparticles Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/acdc2ee6cfb74183b98bce98736abf48
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spelling	oai:doaj.org-article:acdc2ee6cfb74183b98bce98736abf482021-12-02T00:40:33ZAntiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection1178-2013https://doaj.org/article/acdc2ee6cfb74183b98bce98736abf482018-12-01T00:00:00Zhttps://www.dovepress.com/antiviral-efficacy-of-nanoparticulate-vacuolar-atpase-inhibitors-again-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Che-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, nanoparticlesHu CMJChen YTFang ZSChang WSChen HWDove Medical PressarticleInfluenza virusVacuolar ATPase inhibitorDiphyllinBafilomycinNanoparticlesMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 8579-8593 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Influenza virus Vacuolar ATPase inhibitor Diphyllin Bafilomycin Nanoparticles Medicine (General) R5-920
spellingShingle	Influenza virus Vacuolar ATPase inhibitor Diphyllin Bafilomycin Nanoparticles Medicine (General) R5-920 Hu CMJ Chen YT Fang ZS Chang WS Chen HW Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection
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
format	article
author	Hu CMJ Chen YT Fang ZS Chang WS Chen HW
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
publishDate	2018
url	https://doaj.org/article/acdc2ee6cfb74183b98bce98736abf48
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Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

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