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Editor, Senior Moderator
Int J Nanomedicine. 2018 Dec 14;13:8579-8593. doi: 10.2147/IJN.S185806. eCollection 2018.
[h=1]Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection.[/h] Hu CJ[SUP]1,[/SUP][SUP]2[/SUP], Chen YT[SUP]3[/SUP], Fang ZS[SUP]1,[/SUP][SUP]3[/SUP], Chang WS[SUP]3[/SUP], Chen HW[SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]Background:[/h] 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.
[h=4]Methods:[/h] In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs' anti-influenza applicability.
[h=4]Results:[/h] 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%.
[h=4]Conclusions:[/h] These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.
[h=4]KEYWORDS:[/h] bafilomycin; diphyllin; influenza virus; nanoparticles; vacuolar ATPase inhibitor
PMID: 30587980 PMCID: PMC6298390 DOI: 10.2147/IJN.S185806
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[h=1]Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection.[/h] Hu CJ[SUP]1,[/SUP][SUP]2[/SUP], Chen YT[SUP]3[/SUP], Fang ZS[SUP]1,[/SUP][SUP]3[/SUP], Chang WS[SUP]3[/SUP], Chen HW[SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]Background:[/h] 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.
[h=4]Methods:[/h] In this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs' anti-influenza applicability.
[h=4]Results:[/h] 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%.
[h=4]Conclusions:[/h] These results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.
[h=4]KEYWORDS:[/h] bafilomycin; diphyllin; influenza virus; nanoparticles; vacuolar ATPase inhibitor
PMID: 30587980 PMCID: PMC6298390 DOI: 10.2147/IJN.S185806
Free full text