Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects 英文参考文献.docVIP

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Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects 英文参考文献.doc

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Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects 英文参考文献

NiclosamideIsaProtonCarrierandTargetsAcidic EndosomeswithBroadAntiviralEffects AndreasJurgeit1,RobertMcDowell2,StefanMoese2,EricMeldrum2,RetoSchwendener3,UrsF.Greber1* 1Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland, 23-V Biosciences Inc., Menlo Park, California, United States of America, 3Institute of MolecularCancerResearch,UniversityofZurich,Zurich,Switzerland Abstract Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihoodofviralresistance.Weidentifiedthesalicylanilideniclosamideasabroadrangeantiviralagenttargetingacidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects.Itsmodeofactionisunknown.Here,weshowthatniclosamide,whichisaweaklipophilicacidinhibitedinfection withpH-dependenthumanrhinoviruses(HRV)andinfluenzavirus.Structure-activitystudiesshowedthatantiviralefficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry + block.NiclosamidedidnotaffectthevacuolarH -ATPase,butneutralizedcoatedvesiclesorsyntheticliposomes,indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interferencewithhostpathwayshasbroadrangeantiviraleffects,andprovidesaproofofconceptforthedevelopmentof host-directedantivirals. Citation:JurgeitA,McDowellR,MoeseS,MeldrumE,SchwendenerR,etal.(2012)NiclosamideIsaProtonCarrierandTargetsAcidicEndosomeswithBroad AntiviralEffects.PLoSPathog8(10):e1002976.doi:10.1371/journal.ppat.1002976 Editor:BenhurLee,UCLA,UnitedStatesofAmerica ReceivedJune30,2012;AcceptedSeptember4,2012;PublishedOctober25,2012 Copyright: ? 2012 Jurgeit et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauth