Nanoparticulate vacuolar ATPase blocker exhibits potent host-targeted antiviral activity against feline coronavirus

Hu, Canbin; Chang, Wei-Shan; Fang, Zih-Syun; Chen, Youting; Wang, Wen-Lin; Tsai, Hsiao-Han; Chueh, Ling-Ling; Takano, Tomomi; Hohdatsu, Tsutomu; Chen, Hui-Wen

doi:10.1038/s41598-017-13316-0

Cited by 55 publications

(69 citation statements)

References 47 publications

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“…Moreover, diphyllin and bafilomycin showed a sustained release profile, which is advantageous toward improving the drugs' pharmacokinetics. In our previous report, we showed that diphyllin nanoparticles could enhance the compound's efficacy against the feline coronavirus, 23 and this study further verified the nanocarriers' effect against influenza virus. Other studies have shown similar benefits upon nanoparticle encapsulation of antivirals.…”

Section: Discussionsupporting

confidence: 68%

“…As the diphyllin nanoparticles were previously shown to be well tolerated in mice, 23 we further examined the applicability of the nanoparticulate V-ATPase inhibitors for influenza treatment in vivo, a mouse model of influenza infection was used. Mice were inoculated intranasally with a nonlethal dose of H1N1 virus and intravenously treated with diphyllin nanoparticles equivalent to 10 µg of diphyllin or empty nanoparticles of equivalent polymer content daily for 3 days ( Figure 6A).…”

Section: Antiviral Efficacy Of Diphyllin Nanoparticles In Vivomentioning

confidence: 99%

“…Previously, we showed that diphyllin, a new class of the V-ATPase inhibitor, 12 is effective in blocking influenza virus infection, 22 and its nanoformulation showed improved safety and effectiveness in inhibiting the feline coronavirus. 23 Toward improving V-ATPase inhibitors for influenza treatment, we herein prepare diphyllin-loaded polymeric nanoparticles comprised of poly(ethylene glycol)-block-poly(lactide-coglycolide) (PEG-PLGA) and examined its efficacy against influenza virus in vitro and in vivo. In parallel, we assessed the applicability of nanoparticle-mediated delivery to the commonly studied bafilomycin.…”

Section: Introductionmentioning

confidence: 99%

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Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Hu¹,

Chen²,

Fang³

et al. 2018

IJN

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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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Section: Discussionsupporting

confidence: 68%

Section: Antiviral Efficacy Of Diphyllin Nanoparticles In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Hu¹,

Chen²,

Fang³

et al. 2018

IJN

Self Cite

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“…Diphyllin is well tolerated in mice [43]. Delivery of diphyllin by nanoparticles increases its antiviral effects on feline CoV and it is also well tolerated in mice [45]. Niclosamide, a salicylanilide, has been used to treat parasitic helminthic infestations in humans for >40 years [46].…”

Section: Targeting Endosomal Membrane Fusionmentioning

confidence: 99%

Repurposing host-based therapeutics to control coronavirus and influenza virus

Wang

2019

Drug Discovery Today

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Teaser This communication focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus.The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.

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“…In reviewing treatment options for FIP, numerous older studies describing potential treatments are mostly based on cases without a confirmed diagnosis of FIP and hampered by the lack of well-controlled clinical trials [14]. Likewise, the use of other reported treatment options is currently only supported by in vitro studies rather than through in vivo clinical studies [15,16,17,18]. Despite recent antiviral studies with GC376 and GS-441524 showing great promise against FIPV in naturally and experimentally infected cats [19,20,21], these agents have not yet obtained registration for veterinary use [22,23].…”

Section: Introductionmentioning

confidence: 99%

Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats

Izes

Norris

et al. 2020

Veterinary Quarterly

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Feline infectious peritonitis (FIP) is a viral-induced, immune-mediated disease of cats caused by virulent biotypes of feline coronaviruses (FCoV), known as the feline infectious peritonitis virus (FIPV). Historically, three major pharmacological approaches have been employed to treat FIP: (1) immunomodulators to stimulate the patient's immune system non-specifically to reduce the clinical effects of the virus through a robust immune response, (2) immunosuppressive agents to dampen clinical signs temporarily, and (3) re-purposed human antiviral drugs, all of which have been unsuccessful to date in providing reliable efficacious treatment options for FIPV. Recently, antiviral studies investigating the broad-spectrum coronavirus protease inhibitor, GC376 and the adenosine nucleoside analogue GS-441524, have resulted in increased survival rates and clinical cure in many patients. However, prescriber access to these antiviral therapies is currently problematic as they have not yet obtained registration for veterinary use. Consequently, FIP remains challenging to treat. The purpose of this review is to provide an update on the current status of therapeutics for FIP. Additionally, due to interest in coronaviruses resulting from the current human pandemic, this review provides information on domesticated cats identified as SARS-CoV-2 positive.

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Nanoparticulate vacuolar ATPase blocker exhibits potent host-targeted antiviral activity against feline coronavirus

Cited by 55 publications

References 47 publications

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Antiviral efficacy of nanoparticulate vacuolar ATPase inhibitors against influenza virus infection

Repurposing host-based therapeutics to control coronavirus and influenza virus

Current status on treatment options for feline infectious peritonitis and SARS-CoV-2 positive cats

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