Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection
| Autor: | Zih Syun Fang, Wei-Shan Chang, You Ting Chen, Hui-Wen Chen, Che Ming Jack Hu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vacuolar Proton-Translocating ATPases Biophysics Pharmaceutical Science Bioengineering Pharmacology Virus Replication Antiviral Agents Virus influenza virus Lignans diphyllin Cell Line Biomaterials 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 Mice Viral Proteins Therapeutic index Dogs Orthomyxoviridae Infections International Journal of Nanomedicine Drug Discovery Influenza Human Animals Humans Benzodioxoles Vacuolar ATPase Enzyme Inhibitors Cytotoxicity Original Research Organic Chemistry Bafilomycin General Medicine Orthomyxoviridae In vitro Titer Drug Liberation Kinetics 030104 developmental biology chemistry Cell culture bafilomycin vacuolar ATPase inhibitor Nanoparticles Macrolides |
| Zdroj: | International Journal of Nanomedicine |
| ISSN: | 1178-2013 1176-9114 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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