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Antiviral Efficacy of Nanoparticulate Vacuolar ATPase Inhibitors Against Influenza Virus Infection

Antiviral Efficacy of Nanoparticulate Vacuolar ATPase Inhibitors Against Influenza Virus Infection

Che-Ming Jack Hu, You-Ting Chen, Zih-Syun Fang, Wei-Shan Chang, Hui-Wen Chen

Int J Nanomedicine. 2018 Dec 14;13:8579-8593.

PMID: 30587980

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP22055227	Diphyllin		22055-22-7	Price

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