冠状病毒Coronavirusl论文-2006 Understanding Biology Using Peptides __ Design and Study of Novel Peptide Inhibitors against the SARS-Coronavirus S.pdf

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1、UnderstandingBiologyUsingPeptidesSylvieE.Blondelle(Editor)AmericanPeptideSociety,2005DesignandStudyofNovelPeptideInhibitorsagainsttheSARS-CoronavirusSpikeProteinZheYan,BrianTripetandRobertS.HodgesDepartmentofBiochemistryandMolecularGenetics.UniversityofColoradoatDenverandHealthScienc

2、esCenter,Aurora,CO,80045,USAIntroductionSevereAcuteRespiratorySyndrome(SARS)isanacuterespiratoryillnesscausedbyinfectionwithanovelcoronavirus(SARS-CoV).InfectionbySARScoronavirusesrequiresfusionoftheviralandcellularmembranes,whichismediatedbytheviralenvelopeSpike(S)glycoproteinandrec

3、eptorsonthetargetcell.TheSproteincontainstwohydrophobicrepeatregions,denotedHRNandHRC,whicholigomerizetheSglycoproteinintoatrimerinthenativestate,andwhenactivatedcollapseintoasix-helixbundlestructuredrivingfusionofthehostandviralmembranes.WeandothershavepreviouslyreportedthattheHRreg

4、ionsofSARS-CoVSproteincanassociatetoformaverystablehelicalsix-strandedstructureandresidues902–950inHRNand1151–1185inHRCwereidentifiedtobecrucialfortheirinteraction[1-4].Duetotheseverityandmortality(10%)witnessedinthefallof2003duringthespreadoftheSARS-CoVpandemic,andthecurrentlackofef

5、fectiveagentsfortheantiviraltherapyofSARS-CoVinfection,ithasbecomeimperativetolearnasmuchaspossibleaboutthisvirusandtheabilitytopreventfutureFig.1.Schematicmodelillustratingtheactionofinfection.AssuccessfullyusedSARS-CoVfusioninhibitorsthattargetHRN.infusioninhibitordesignforHIV[5],p

6、eptidesderivedfromHRCcanbindtothetransientlyexposedHRNcoiled-coiltrimerandblocktheformationofthesix-helicalbundle(Fig.1),whichultimatelyleadstoalossofmembrane-fusionactivity.Inthisstudy,HRN(902-950)peptideofSARS-CoVSproteinwaschosenasthetargetfortestingtheinteractionofHRCanalogs.The3

7、6-residueHRCpeptide(1150-1185)waschosenastheregiontodesignaseriesofHRCanalogs,inordertoincreasetheirstabilityandbindingaffinitywithHRN.Thesesubstitutions/modificationsinvolved:(1)increasinghelicalpropensity(HRC2andHRC4);(2)increasinghydrophobicityinthehydrophobiccore(HRC1andHRC3);and

8、(3)introduci