HUI-WEN CHENCheng, J.X.J.X.ChengLiu, M.-T.M.-T.LiuKing, K.K.KingPeng, J.-Y.J.-Y.PengZhang, X.-Q.X.-Q.ZhangWang, C.-H.C.-H.WangShresta, S.S.ShrestaSchooley, R.T.R.T.SchooleyLiu, Y.-T.Y.-T.Liu2018-09-102018-09-102013http://www.scopus.com/inward/record.url?eid=2-s2.0-84884578114&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/377241An influenza pandemic poses a serious threat to humans and animals. Conventional treatments against influenza include two classes of pathogen-targeting antivirals: M2 ion channel blockers (such as amantadine) and neuraminidase inhibitors (such as oseltamivir). Examination of the mechanism of influenza viral infection has shown that endosomal acidification plays a major role in facilitating the fusion between viral and endosomal membranes. This pathway has led to investigations on vacuolar ATPase (v-ATPase) activity, whose role as a regulating factor on influenza virus replication has been verified in extensive genome-wide screenings. Blocking v-ATPase activity thus presents the opportunity to interfere with influenza viral infection by preventing the pH-dependent membrane fusion between endosomes and virions. This study aims to apply diphyllin, a natural compound shown to be as a novel v-ATPase inhibitor, as a potential antiviral for various influenza virus strains using cell-based assays. The results show that diphyllin alters cellular susceptibility to influenza viruses through the inhibition of endosomal acidification, thus interfering with downstream virus replication, including that of known drug-resistant strains. In addition, combinatorial treatment of the host-targeting diphyllin with pathogen-targeting therapeutics (oseltamivir and amantadine) demonstrates enhanced antiviral effects and cell protection in vitro. ? 2013 Elsevier B.V.Amantadine; Diphyllin; Influenza virus; Oseltamivir; Vacuolar ATPase inhibitor[SDGs]SDG3adenosine triphosphatase; amantadine; diprophylline; oseltamivir; 1,3 benzodioxole derivative; amantadine; antivirus agent; diprophylline; enzyme inhibitor; herbaceous agent; lignan; oseltamivir; proton transporting adenosine triphosphate synthase; 1,3 benzodioxole derivative; antivirus agent; enzyme inhibitor; herbaceous agent; lignan; proton transporting adenosine triphosphate synthase; adenosine triphosphatase inhibitor; diprophylline; acidification; animal cell; antiviral activity; article; avian influenza virus; cell protection; cell viability; controlled study; cytopathogenic effect; cytotoxicity; Dengue virus 2; drug cytotoxicity; endosome; hemagglutination test; IC 50; in vitro study; infection sensitivity; influenza; Influenza virus; Influenza virus A H1N1; Influenza virus A H3N2; membrane fusion; nonhuman; pH; priority journal; protein expression; virion; virus culture; virus entry; virus replication; angiosperm; animal; chemistry; drug antagonism; drug combination; drug effect; enzymology; human; influenza; Influenza virus; metabolism; Orthomyxovirus; physiology; Vacuolar ATPase inhibitor; virology; antagonists and inhibitors; drug effects; enzymology; Influenza, Human; Orthomyxovirus; cell assay; fluorescence microscopy; real time polymerase chain reaction; Western blotting; Amantadine; Diphyllin; Influenza virus; Oseltamivir; Vacuolar ATPase inhibitor; Amantadine; Angiosperms; Animals; Antiviral Agents; Benzodioxoles; Drug Therapy, Combination; Drugs, Chinese Herbal; Endosomes; Enzyme Inhibitors; Humans; Influenza, Human; Lignans; Membrane Fusion; Orthomyxoviridae; Oseltamivir; Vacuolar Proton-Translocating ATPases; Virus Replication; Amantadine; Angiosperms; Animals; Antiviral Agents; Benzodioxoles; Drug Therapy, Combination; Drugs, Chinese Herbal; Endosomes; Enzyme Inhibitors; Humans; Influenza, Human; Lignans; Membrane Fusion; Orthomyxoviridae; Oseltamivir; Vacuolar Proton-Translocating ATPases; Virus Replicationjournal article10.1016/j.antiviral.2013.06.014