Antiviral efficacy of nanoparticulate vacuolar ATPase Inhibitors Against Influenza virus infection
Journal
International Journal of Nanomedicine
Journal Volume
13
Date Issued
2018-01-01
Author(s)
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.
Subjects
influenza virus; vacuolar ATPase inhibitor; diphyllin; bafilomycin; nanoparticles
SDGs
Other Subjects
bafilomycin; diprophylline; macrogol; nanoparticle; polyglactin; 1,3 benzodioxole derivative; antivirus agent; bafilomycin A; diprophylline; enzyme inhibitor; lignan; macrolide; proton transporting adenosine triphosphate synthase; viral protein; animal cell; animal experiment; animal model; animal tissue; antiviral activity; Article; body weight loss; controlled study; disease severity; drug cytotoxicity; drug delivery system; drug efficacy; drug release; drug structure; drug therapeutic index; female; IC50; in vitro study; in vivo study; influenza; Influenza virus; mouse; mouse model; nanoencapsulation; nonhuman; virus load; virus strain; animal; antagonists and inhibitors; cell line; chemistry; dog; drug effect; human; influenza; kinetics; metabolism; Orthomyxoviridae; orthomyxovirus infection; physiology; ultrastructure; virology; virus replication; Animals; Antiviral Agents; Benzodioxoles; Cell Line; Dogs; Drug Liberation; Enzyme Inhibitors; Humans; Influenza, Human; Inhibitory Concentration 50; Kinetics; Lignans; Macrolides; Mice; Nanoparticles; Orthomyxoviridae; Orthomyxoviridae Infections; Vacuolar Proton-Translocating ATPases; Viral Proteins; Virus Replication
Publisher
DOVE MEDICAL PRESS LTD
Type
journal article