Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Abstract

BackgroundInfluenza 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.MethodsIn this study, we report that nanoparticle encapsulation of diphyllin and bafilomycin improves the drugs’ anti-influenza applicability.ResultsUsing 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%.ConclusionsThese results demonstrate the potential of the nanoparticulate V-ATPase inhibitors for host-targeted treatment against influenza.

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“…An appropriately designed nanoparticle-antiviral drug combination can be expected to enhance the effect of the compounds in several ways (e.g. facilitate interaction with the viral particles, interfere with their entry into cells, increase bioavailability and stability of the formulation, and release antiviral agents in a controlled manner) [67,151,152]. Biocompatible nanoparticles may show broad-spectrum antiviral activity [153].…”

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“…It resulted in efficient COV replication blockage in fcwf-4 cells. 39 , 40 Second, inhibition of the synthesis of viral RNA was reached by using the various types of Ag nanomaterials mentioned above. 41 − 43 Third, antiviral activity could be associated with a certain level of cellular immune response, as highlighted by the expression of pro-inflammation cytokines following cellular exposure to Ag NP.…”

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“…Also, poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG)-PLGA) diblock copolymers have been studied to coupling two ATPase inhibitors (dyphylline and bafilomycin) for antiviral activity. The intravenous administration of PLGA nanocarriers improved the anti-influenza applicability of dyphylline in H1N1 infection, exhibiting controlled drug release in the lungs and providing significant protection against lethal doses of the virus in vitro and in vivo models (Hu et al, 2018).…”