Cargando…
Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection
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 antivira...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298390/ https://www.ncbi.nlm.nih.gov/pubmed/30587980 http://dx.doi.org/10.2147/IJN.S185806 |
_version_ | 1783381309660332032 |
---|---|
author | Hu, Che-Ming Jack Chen, You-Ting Fang, Zih-Syun Chang, Wei-Shan Chen, Hui-Wen |
author_facet | Hu, Che-Ming Jack Chen, You-Ting Fang, Zih-Syun Chang, Wei-Shan Chen, Hui-Wen |
author_sort | Hu, Che-Ming Jack |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6298390 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62983902018-12-26 Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection Hu, Che-Ming Jack Chen, You-Ting Fang, Zih-Syun Chang, Wei-Shan Chen, Hui-Wen Int J Nanomedicine Original Research 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. Dove Medical Press 2018-12-14 /pmc/articles/PMC6298390/ /pubmed/30587980 http://dx.doi.org/10.2147/IJN.S185806 Text en © 2018 Hu et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Hu, Che-Ming Jack Chen, You-Ting Fang, Zih-Syun Chang, Wei-Shan Chen, Hui-Wen Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title | 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_short | Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection |
title_sort | antiviral efficacy of nanoparticulate vacuolar atpase inhibitors against influenza virus infection |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298390/ https://www.ncbi.nlm.nih.gov/pubmed/30587980 http://dx.doi.org/10.2147/IJN.S185806 |
work_keys_str_mv | AT huchemingjack antiviralefficacyofnanoparticulatevacuolaratpaseinhibitorsagainstinfluenzavirusinfection AT chenyouting antiviralefficacyofnanoparticulatevacuolaratpaseinhibitorsagainstinfluenzavirusinfection AT fangzihsyun antiviralefficacyofnanoparticulatevacuolaratpaseinhibitorsagainstinfluenzavirusinfection AT changweishan antiviralefficacyofnanoparticulatevacuolaratpaseinhibitorsagainstinfluenzavirusinfection AT chenhuiwen antiviralefficacyofnanoparticulatevacuolaratpaseinhibitorsagainstinfluenzavirusinfection |