Peptide Inhibitors of Dengue-Virus Entry Target a Late-Stage Fusion Intermediate 英文参考文献.docVIP

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Peptide Inhibitors of Dengue-Virus Entry Target a Late-Stage Fusion Intermediate 英文参考文献.doc

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Peptide Inhibitors of Dengue-Virus Entry Target a Late-Stage Fusion Intermediate 英文参考文献

PeptideInhibitorsofDengue-VirusEntryTargetaLate- StageFusionIntermediate AaronG.Schmidt1,PriscillaL.Yang2,StephenC.Harrison1,3* 1Jack and Eileen Connors Laboratory of Structural Biology, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America, 2Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, United States of America,3HowardHughesMedicalInstitute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Themechanismofmembranefusionby‘‘classII’’viralfusionproteinsfollowsapathwaythatinvolveslarge-scaledomain rearrangementsoftheenvelopeglycoprotein(E)andatransitionfromdimerstotrimers.Therearrangementisbelievedto proceed by an outward rotation of the E ectodomain after loss of the dimer interface, followed by a reassociation into extendedtrimers.The,55-aa-residue,membraneproximal‘‘stem’’canthenzipupalongdomainII,bringingtogetherthe transmembranesegmentsoftheC-terminusandthefusionloopsatthetipofdomainII.Wefindthatpeptidesderivedfrom the stem of dengue-virus E bind stem-less E trimer, which models a conformational intermediate. In vitro assays demonstratethatthesepeptidesspecificallyblockviralfusion.Thepeptidesinhibitinfectivitywithpotencyproportionalto theiraffinityfortheconformationalintermediate,evenwhenfreepeptideisremovedfromapreincubatedinoculumbefore infectingcells.Weconcludethatpeptidesbindvirionsbeforeattachmentandarecarriedwithvirionsintoendosomes,the compartment in which acidification initiates fusion. Binding depends on particle dynamics, as there is no inhibition of infectivityifpreincubationandseparationareat4uCratherthan37uC.Weproposeatwo-stepmodelforthemechanismof fusioninhibition.Targetingaviralentrypathwaycanbeaneffectivewaytoblockinfection.Ourdata,whichsupportand extend proposed mechanisms for how the E conformational change promotes membrane fusion, suggest strategies for inhibitingflavivirusentry. Citation:S