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 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.
['Hu|Che-Ming Jack|CJ|', 'Chen|You-Ting|YT|', 'Fang|Zih-Syun|ZS|', 'Chang|Wei-Shan|WS|', 'Chen|Hui-Wen|HW|']
D000818:Animals D000998:Antiviral Agents D052117:Benzodioxoles D002460:Cell Line D004285:Dogs D065546:Drug Liberation D004791:Enzyme Inhibitors D006801:Humans D007251:Influenza, Human D020128:Inhibitory Concentration 50 D007700:Kinetics D017705:Lignans D018942:Macrolides D051379:Mice D053758:Nanoparticles D009975:Orthomyxoviridae D009976:Orthomyxoviridae Infections D025262:Vacuolar Proton-Translocating ATPases D014764:Viral Proteins D014779:Virus Replication
vacuolar ATPase inhibitor influenza virus diphyllin bafilomycin nanoparticles