Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus.docVIP

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Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus.doc

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Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus

AntiviralLectinsfromRedandBlue-GreenAlgaeShow PotentInVitroandInVivoActivityagainstHepatitisC Virus YutakaTakebe1,CarrieJ.Saucedo2,GarryLund3,RieUenishi1,SaikiHase1,TakayoTsuchiura1, NormanKneteman3,KoreenRamessar4,D.LorneJ.Tyrrell3,MasayukiShirakura5¤,TakajiWakita5, JamesB.McMahon4,BarryR.O’Keefe4* 1AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan, 2Molecular Targets Laboratory, SAIC-Frederick, Frederick, Maryland, United States of America,3KMTHepatech,Edmonton,Alberta,Canada,4MolecularTargetsLaboratory,CenterforCancerResearch,NationalCancerInstitute,Frederick,Maryland,United StatesofAmerica,5VirologyII,NationalInstituteofInfectiousDiseases,Tokyo,Japan Abstract HepatitisCvirus(HCV)infectionisasignificantpublichealthproblemwithover170,000,000chroniccarriersandinfection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimatedtoresultin,10,000deathsintheUnitedStatesintheyear2011.CurrenttreatmentoptionsforHCVinfectionare limitedtoPEG-ylatedinterferonalpha(IFN-a),thenucleosideribavirinandtherecentlyapprovedHCVproteaseinhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with proteaseinhibitorshasbeenshowntoresultintherapidemergenceofdrug-resistantvirus.Herewereporttheactivityof twoproteins,originallyisolated fromnaturalproduct extracts,which demonstrateloworsub-nanomolar invitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteinsE1andE2andblockviralentryintohumanhepatocytes.Inaddition,wedemonstratethatthemostpotentof theseagents,theproteingriffithsin,isreadilybioavailableaftersubcutaneousinjectionandshowssignificantinvivoefficacy inreducingHCVviraltitersinamousemodelsystemwithengraftedhumanhepatocytes.TheseresultsindicatethatHCV viralentryinhibitorscanbeaneffectivecomponentofanti-HCVtherapyandthattheseproteinss