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首页 流感病毒药物

流感病毒药物.pdf

流感病毒药物

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简介:本文档为《流感病毒药物pdf》,可适用于自然科学领域

egAvailableonlineatwwwsciencedirectcomir(HA)andneuraminidase(NA)InfluenzaBviruseshavedivergedintotwomajorantigeniclineagesinthes(VictorialikeandYamagatalike)ViralentryrequiresattachmentoftheHAproteintoterminalsialicacidresidueslinkedtogalactoseviaa,linkagesora,linkagesfollowedbyclathrindependentendocytosisandmacropinocytosisUnderacidicpH,theHAproteinundergoesconformationalchangestoexposethefusionpeptide,whichmediatesfusionbetweentheMionchannelblockersAdamantanederivatives,amantadineandrimantadine(Figure)inhibittheprotonconductivityoftheMionchannelofinfluenzaAvirusesbutpossessnoinhibitoryeffectfortheionchannelsofinfluenzaBviruses,astheAMandBMarefunctionalhomologswithoutapparentsequencehomologyInhibitionoftheMionchannelactivitypreventsuncoatingoftheinfluenzaAvirusesattheearlyphaseoftheviralreplicationandmayCurrentOpinioninVirology,:ndashwwwsciencedirectcomCurrentandnovelantiviralstratinfectionHuiLingYenInfluenzaAandBvirusesaremajorcausesforrespiratoryinfectionsinchildrenandadultsViralandhostfactorsdetermineclinicalmanifestationswhichrangefromselfresolvinguncomplicatedinfections,severeviralorbacterialsecondarypneumonia,todeathEmergenceoftransmissibleresistantvariantsandtimedependenteffectivenessarethemajorchallengesforthecurrentlyapprovedantivirals,Mionchannelblockersandneuraminidase(NA)inhibitorsFavipiravirthatinhibitstheRNAdependentRNApolymeraseofmultipleRNAvirusesisapprovedinJapanagainstinfluenzastrainsresistanttoavailableantiviralsWithexpandedknowledgeonviralnucleoprotein(NP)andpolymerasestructures,novelsmallmoleculeinhibitorstargetingNPoligomerformation,PAendonucleasedomain,andthePBcapbindingdomainarebeingdevelopedCombinationtherapywithdifferentantiviralcompoundsorwithhostimmuneresponsemodulatorsmayfurtherbenefitclinicaloutcomesAddressSchoolofPublicHealth,LiKaShingFacultyofMedicine,TheUniversityofHongKong,HongKongSpecialAdministrativeRegionCorrespondingauthor:Yen,HuiLing(hyenhkuhku)CurrentOpinioninVirology,:ndashThisreviewcomesfromathemedissueonAntiviralstrategiesEditedbyRaymondFSchinaziandErikdeClercqForacompleteoverviewseetheIssueandtheEditorialAvailableonlinerdJunehttp:dxdoiorgjcoviroPublishedbyElsevierBVIntroductionInfluenzaAandBvirusesaremembersoftheOrthomyxoviridaewitheightsegmentedsinglestrandednegativesenseRNAgenomesInfluenzaAvirusesaregroupedintosubtypesbythesurfaceglycoproteinshemagglutininScienceDiesforinfluenzaviralenvelopeandendosomemembranetoreleaseviralribonucleoproteins(RNPs)TheMionchannelsmediateprotonflowfromtheendosomeintotheinterioroftheviriontodissociateRNPsfromtheMmatrixproteinsTheRNPs,consistingofheterotrimericinfluenzapolymeraseproteins(PB,PB,andPA)andtheviralRNAgenomeencapsidatedbythenucleoprotein(NP),aretransportedintothenucleusforviralmRNAsynthesisandgenomereplicationmediatedbytheRNAdependentRNApolymerasePBproteinThecapbindingactivityofthePBproteinandtheendonucleaseactivityofthePAproteinarecriticalforcapsnatchingandmRNAsynthesisThemRNAsaretransportedtothecytoplasmforproteinsynthesisTheHA,NAandMproteinsaresynthesizedattheendoplasmicreticulumandaretransportedviathetransGolginetworktotheapicalcellmembraneTheMmatrixandthenucleusexportprotein(NEP)mediatenucleusexportationoftheRNPstothecytoplasmfollowedbyfinalassemblyandbuddingfromtheapicalcellmembraneViralreleaseandspreadintherespiratorytractarefacilitatedbythesialidaseactivityoftheNAproteinsClinicalmanifestationsofinfluenzainfectionsmayrangefromselfresolvinguncomplicatedinfectionstocomplicationsinthehighriskpopulationsAmongpatientswithsevereinfections,highviralloadsandelevatedproinflammatorycytokinesaccompaniedbyincreasedimmunecellinfiltrationscanbeobserved,suggestingthattheclinicaloutcomeisdeterminedbycomplexviralandhostdeterminantsOverall,theannualepidemicsandperiodicglobalpandemicscausedbyinfluenzavirusesmayleadtondashtondashmillionglobalmortality,respectively��,EffectivepharmaceuticalinterventionsarethereforeindispensableTodate,threedifferentclassesofantiviralcompoundsthateachtargettheMionchannel,NAenzymesite,andtheRNAdependentRNApolymerasehavebeenapprovedforclinicaluseEfficacyandresistanceofcurrentlyapprovedantiviralcompoundsectAntiviralstrategiesforinfluenzaYenallowthelowpHtotriggerconformationalchangeofthenewlysynthesizedHAatthetransGolginetworkInadditiontothepotentialCNSsideeffects,fullytransmissibleresistancevariantsemergerapidlyfrompatientsaftertreatmentSurveillancestudiesreportedasteadyincreaseoftheresistantvariantsamongtheseasonalHNvirusessincewhichreachedamongglobalHNisolatesinndash,,althoughamantadineandrimantadinewerestilleffectiveagainstthemajorityoftheseasonalHNvirusSince,amantadineandrimantadinearenotrecommendedforclinicaluseduetotheemergenceofthenewpandemicHN(pdmHN)virus,whichnaturallycarriestheMSNmutationthatconfersresistancetobothdrugsSystematicreviewsuggestslimitedbenefitofamatandineandrimantadineinpreventing,treating,andshorteningthedurationofinfluenzaAinfectioninchildrenandtheelderlyFigureNHNHAmantadineRimantadineCurrentOpinioninVirologyChemicalstructuresofamantadineandrimantadineAmantadineandrimantadineblockprotonflowthroughMionchannelsofinfluenzaAvirusesNAinhibitorsTheNAofinfluenzaAandBvirusesshareaminoacidsequencehomologyandarehomotetramersofkDawithsialidaseactivityatacidicpH(ndash)PhylogeneticanalysisfurtherseparatestheNAofinfluenzaAvirusesintoGroup(N,N,N,N)andGroup(N,N,N,N,N)Theenzymesitessharesimilarstructureandconservedresiduesasfoundinotherviralandbacterialsialidases(R,D,R,R,E,R,R,andY,Nnumbering)Additionally,influenzaAandBvirusesshareconservedframeworkresidues(E,R,W,S,DN,I,E,H,E,N,E)ThedevelopmentofNAinhibitorswasinitiatedintheswiththenaturalinhibitordeoxy,dehydroNacetylneuraminicacid(NeuAcen),atransitionstateanalogofinfluenzaNA,ThedetailstructureoftheNAconservedenzymesiteinteractingwithsialicacidorNeuAcenfacilitatedthestructuralbaseddesignofwwwsciencedirectcomthecurrentlyapprovedNAinhibitorsndashSince,fourcompetitiveNAinhibitors(zanamivir,oseltamivircarboxylate,peramivir,andlaninamivir)havebeenapprovedfortreatmentandprophylaxisforinfluenzaAandBinfectionsTheseinhibitorspossessdifferentsidechainmodificationstoimprovebioavailabilityandbindingtotheNAactivesite(Figure)ZanamivirreplacedthehydroxylgroupofNeuAcenwiththebasicguanidinogrouptoimprovebindingthroughtheterminalnitrogenswiththeNAresiduesEandE,zanamivirisadministeredbyoralinhalationTofurtherimproveoralbioavailability,oseltamivircarboxylateandperamivirweredesignedbasedonnoncarbohydratetemplates,withcyclohexenesandcyclopentanes,respectivelyOseltamivircarboxylatefurtherdiffersfromzanamivirbythebulkyhydrophobicpentylethersidechainthatreplacedtheglycerolsidechainandtheaminogroupToaccommodatethehydrophobicsubstitutionattheposition,NAresidueEneedtoreorientandformasaltbridgewithRandresultsintheformationofahydrophobicpocketPeramivirdiffersfromzanamivirandoseltamivircarboxylatebythecyclopentaneringinaddition,itpossessesaguanidinogroupthatresembleszanamivir,andahydrophobicsidechainthatresemblesoseltamivircarboxylate�thedesignleadstomultiplebindinginteractionsofperamivirattheNAenzymesiteInhumans,theoralbioavailabilitywaspoorandparenteralformulationsviaintramuscularorintravenous(IV)injectionswerepursuedCurrently,itisapprovedinJapan,Korea,andUSAfortreatmentofacuteuncomplicatedinfluenzainadultsbyIVinjectionLaninamivirisalongactingNAinhibitorcontainingaguanidinogroupandamethoxygroupTheprodruglaninamiviroctanoateisprocessedintolaninamivirinthelungswithahighretentiontimethisprovidesthelonglastingantiinfluenzaactivityafterasingleintranasaladministration,LaninamiviriscurrentlyonlyapprovedforclinicaluseinJapanInaddition,thenewlydeveloped,difluorosialicacid(DFSA)basedNAinhibitorsthatformstabilizedcovalentintermediateatNAenzymesiteshowedsignificantlyimprovedinhibitoryeffectagainstinfluenzaAandBvariantsresistanttocurrentlyapprovedNAinhibitors�ThesensitivityandresistanceprofileofinfluenzaAandBvirusesNAproteinsaredeterminedbytheinteractionsbetweentheNAconservedresidueswiththeNAinhibitorsofdifferentsidechainmodificationsInfluenzaAvirusesaremoresusceptibletothefourapprovedNAinhibitorsthaninfluenzaBviruseswithlowerICvaluesbytheenzymebasedNAinhibitionassaysThepdmHNvirusismarginallymoresusceptibletozanamivir,peramivir,andlaninamivirwiththeguanidinogroupthantheHNvirus,possiblyduetotheloopcavitypossessedbytheGroupNASimilarly,theresistanceprofileofN,N,andinfluenzaBNAproteinscanalsobedifferentiatedThemutationsthatCurrentOpinioninVirology,:ndashAntiviralstrategiesHOvirFigureOHOHOHOHOHOOHOOOOOOOONHNHNHNHNHNHHHHHHHHNeuAcenZanamiPeramivirconfertodrugresistanceareoftenlocatedattheconservedenzymeorframeworkresidues�however,mutationatthemonomerndashmonomerinterfacehasbeenalsoreportedtoconferresistanceFurthermore,somemutationsconfercrossresistancetomultipleNAinhibitorswhilesomemutationsonlyleadtoreducedsusceptibilityofoneNAinhibitoraloneForN,theHYmutationismostcommonlyobservedmutationclinically�itleadstohighlyreducedsusceptibility(folddifferenceinIC)tooseltamivirandperamivirbutremainsusceptibleforzanamivirandlaninamivirInaddition,aminoacidchangesinresidue(fromItoKTR)werereportedinpdmHNvirustoconferreducedsusceptibility(ndashfolddifferenceinIC)tooseltamivirthecombinationofIRandHYmutationsleadtocrossresistancetoallfourNAinhibitorsForN,theRKandEVmutationsarethemostcommonlyreportedmutationsclinically�,,TheRKmutationleadstohighlyreducedsusceptibilitytooseltamivirandperamivir,reducedsusceptibilityforzanamivir,andfoldincreaseinIC(normalinhibition)forlaninamivirtheEVmutationleadstohighlyreducedsusceptibilityforoseltamivirbutremainsusceptibletootherdrugs,TheNSmutationhasbeenidentifiedinbothN(HNandpdmHNclinicalOHNHNHNHChemicalstructuresofNeuAcenandthecurrentlyapprovedNAinhibitorsNeuAcen,atransitionstateanalogofsialicacidwithdifferentmodificatiocarboxylateandperamivirweredesignedbasedonnoncarbohydratetempCurrentOpinioninVirology,:ndashOHOHOHOHOHOHHOOOOONHNHNHNHNHLaninamivirOseltamivircarboxylateisolates)andN(HNclinicalisolates)thatconferresistancetooseltamivir,,ForinfluenzaB,RK,DNorILmutationshavebeendetectedfromimmunocompromisedpatientsafterreceivingprolongedNAinhibitortreatmentndashThemutationsfoundinclinicalspecimenwithreducedsusceptibilitytoNAinhibitorshavebeensummarizedbyWorldHealthOrganization(WHO)andarereportedannuallybytheWHOcollaboratingcenters,Ingeneral,thestructurebaseddesignlimitstheemergenceofresistantvariantswithuncompromisedNAenzymefunction,asmutationsattheconservedNAresiduesthatalterbindingtotheNAinhibitorswillsimilarlyreducebindingtosialicacidsAlthoughresistantvariantscanbeidentifiedfrompatientsafterNAinhibitortreatment,especiallyamongchildrenwithhigherviralloadthanadults,ndashorimmunocompromisedpatientswithprolongedviralsheddingndash,ndash,theresistanceratewerelowatthecommunitylevelbeforeduetothelackoftransmissionofdrugresistantvariantsSeasonalHNinfluenzavariantwithanHYNAmutation(Nnumbering)thatconfersresistancetooseltamivircarboxylatewasreportedatincreasingpercentagefrompatientswithoutpriortreatmentinndashinfluenzaseasonandOONHCurrentOpinioninVirologyThestructuralbasedesignedNAinhibitorsweredevelopedbasedonnsatCandCTofurtherimproveoralbioavailability,oseltamivirlatesofcyclohexenesandcyclopentaneswwwsciencedirectcomspreadgloballyasthedominantHNstrainbytheendofStudiesshownthatNAmutationsemergedinchronologicalorderbefore(VM,RQ,KE,DN)andpostto(DG)theacquisitionoftheHYmutationfacilitatedtherestorationoftheNAfunction�,ndashBecauseofthemechanismofactionoftheNAinhibitorsduringviralreplication,clinicaleffectivenessisassociatedwithtimelyadministration,preferablywithinhoursofsymptomonset,��,,althoughtreatmentstartedwithinndashdaysalsoimprovedsurvivalinadultpatientshospitalizedforseasonalinfluenza��RecentsystemAntiviralstrategiesforinfluenzaYenaticreviewsonrandomizedcontroltrialsreportedthatoseltamivirtreatmentreducedthetimetosymptomalleviationinadultsandhealthychildren�,�,decreasedtheriskforlowerrespiratorytractcomplicationsandhospitaladmissioninadults�,whilezanamivirreducedthetimetosymptomalleviationinadultsNucleosideanalogsfortheRNAdependentRNApolymeraseFavipiravir(T,fluorohydroxypyrazinecarboxamide)isanucleosideanalogthatinhibitstheRNAdependentRNApolymeraseactivityforinfluenzaandotherRNAviruses(Figure)TheRTPformofTwasshowntocompetitivelyinhibitATPandGTPincorporationintotheRNAtranscriptsandpreventRNAelongationInaddition,lethalmutagenesiscanbeanalternativeantiviralmechanismofactionforRNAvirusesasTshowedmutagenesiseffectforinfluenzaAvirusinvitroandfornorovirusinvivoInspiteofextensivesearch,favipiravirresistantvarianthasonlybeenselectedforthechikungunyavirustodatewithasinglemutationataconservedresidueoftheRNAdependentRNApolymeraseDespiteitspotentialtetratogenicandembryotoxicpotential,favipiravirwasapprovedininJapanagainstnovelorreemerginginfluenzavirusinfectionsunderconditionsthatotherantiinfluenzavirusdrugsareineffectiveinaddition,itwasalsoapprovedinJapanforthetreatmentofEbolaFigureOHOHOHOHOOONHNHNFNNNNFavipiravirRibavirinCurrentOpinioninVirologyNucleosideanalogsthatinhibitRNAdependentRNApolymeraseFavipiravirandribavirinarenucleosideanalogsthatshownbroadspectruminhibitoryactivityformultipleRNAviruseswwwsciencedirectcomSimilartofavipiravir,ribavirinisaguanosineanalogwithbroadrangeantiviralactivityagainstRNAandDNAviruses(Figure)Therearetwomajorpotentialantiviralactivities,oneisforthemonophosphateformtocompetewiththecellularinosinemonophosphatefortheIMPdehydrogenaseleadingtodepletionofthecellularGTPpooltheotherviathetriphosphateformthatisincorporatedintotheRNAtranscript,whichmayblockRNAelongationandmayalsoleadtothemutagenesiseffectAlthoughribavirinexhibitedantiviralactivityforinfluenzaAandBvirusesinvitroandinanimalmodels,clinicalusageofribavirinforinfluenzatreatmenthasbeenlimitedDependingonthedoseandviralstrain,combinationtherapywithribavirinandNAinhibitorsmayleadtosynergisticoradditiveeffectsinanimalmodelsNovelinhibitorsthatblockinfluenzaRNPfunctionInthepastfewyears,thedetailstructuresofinfluenzaNPandpolymeraseproteinsndashhavefacilitatedthestructuralbaseddesignorrefinementofinhibitorsthatblockinfluenzaRNPfunctionNPinhibitorsThetransportationofnewlysynthesizedNPproteinsfromthecytoplasmtothenucleus,theformationsofNPoligomerstoencapsidatethenewlysynthesizedviralRNA,andnucleusexportofviralRNPareessentialduringinfluenzareplicationCurrentantiviralstrategiesfocusedoninterferingtheNPndashNPinteraction,NPndashRNAinteraction,andNPnucleusexportsignal(NES)fornucleusexportationofinfluenzaAvirusNucleozin(Figure)wasidentifiedthroughhighthroughputscreeningsndashitinducesNPhighorderoligomerformationthatinhibitsNPtransportationfromthecytoplasmintothenucleusAsanalternativestrategy,disruptingNPoligomerformationbytargetingNPresiduesERsaltbridgeformationhasbeenproposedandvalidatedinvitrousingpeptideorsmallmoleculesidentifiedthroughmoleculardockingNaproxen(Figure),anonsteroidalantiinflammatorydrugthatinhibitscyclooxygenaseIandII,wasidentifiedthroughvirtualscreeningtodisrupttheNPndashRNAinteractionwithitsantiviralactivityvalidatedinvitroandinthemousemodelInaddition,RK(Figure)wasidentifiedfromhighthroughputscreeningthatbindstoaNPfunctionaldomaincriticalforNPndashNPandNPndashRNAinteractionsaswellastheNESndashCRMinteractionfornucleusexportationSmallmoleculesthatinhibitsPBcapbindingandPAendonucleaseactivitiesInfluenzamRNAsynthesisrelyonthelsquocapsnatchingrsquomechanismwhichrequiresbindingofviralPBproteintothehostpremRNAcapstructurefollowedbythePAendonucleaseactivitytogeneratethecappedoligonucleotidesthatwouldbeusedasprimersforviralmRNAtranscriptionThecapsnatchingmechanismissharedCurrentOpinioninVirology,:ndashAntiviralstrategiesFigureOOOONOHOOHOOndashNNCINNNucleozinNaproxenRKCurrentOpinioninVirologyInhibitorsthatinterfereNPndashNPorNPndashRNAinteractionsNucleozinandRKwereidentifiedviahighthroughputscreeningnaproxenthatinhibitscyclooxygenaseIandIIwereidentifiedthroughvirtualscreeningamongsegmentednegativestrandedRNAvirusesintheOrthomyxoviridae,BunyaviridaeandArenaviridae�Anoralbioavailableazaindolebasedinhibitor(VX)wasidentifiedthroughscreeningtocompetitivelybindtothemethylGTPbindingsiteofPBproteintoinhibitcapbindingactivity(Figure)Inthemousemodel,VXwaseffectiveunderprophylaxisorpostexposuretreatmentregimens,withsurvivalachieveduptohourspostinfectionAnMImutationwasidentifiedinoutofpatientsfromahumanchallengestudyfollowedbyVXtreatmenttheresistantvirusshowedcompromisedgrowthinvitroInaddition,resistantvariantwasdetectedaftertwopassagesinvitrowithanFSmutationinPBInfluenzaBviruseslackingtheFinPBalsoshowedpoorbindingtoVX,suggestingtheconformationaldifferencesbetweeninfluenzaAandBvirusesatthecapbindingdomaincouldbeachallengeforthedrugdesignCurrently,VXisunderphasebtrialTheconservedresiduesatthePANterminalendonucleasedomainposeanothertargetfordrugdesignBeforethedetailPANterminalstructurewasavailable,multipleFigureVXFFONNNNHHNOHSmallmoleculesthatinhibitsPBcapbindingandPAendonucleaseactivitCurrentOpinioninVirology,:ndashchemicalcompoundshavebeenreportedtoinhibittheendonucleaseactivityforcapsnatchingsince,DetailedstructuralinsightsshowedthattheNhydroxyimideandthesubstituted,dioxobutanoicacidinhibitorschelateswithtwomanganeseionsattheendonucleaseactivesite,AlthoughresistantvariantswerenotidentifiedafterserialpassagesunderthecompoundL,(Figure),onemostpotentsubstituted,dioxobutanoicacidinhibitorinvitro,mutagenesisstudyidentifiedpotentialresiduesinPAproteinsthatmayconferresistanceCombinationtherapyThebenefitofcombinationtherapyincludesreducingtheemergenceofresistantvariantsandprovidingpotentialadditiveorsynergisticeffectoftheantiviralcompoundsHowever,clinicalapplicationsofcombinationtherapyagainstinfluenzainfectionshavebeenlimited,possiblyduetothefewclassesofantiviralsapprovedforclinicaltreatmentCombinationtherapyofoseltamivirandzanamivirtreatmentintworandomizedcontroltrialsamongpatientsinfectedwithhumanHNorpdmHNvirusesfailedtodemonstratesuperiorefficacythantheLOONOHHObullHCICICurrentOpinioninVirologyywwwsciencedirectcomAntiviralstrategiesforinfluenzaYenmonotherapyalone,FavipiravirandoseltamivirshowedsynergisticeffectwhilegivenatlowdosesinmicefavipiravirandperamivirshowedsynergyagainstapdmHNvariantwithanHYmutationinmiceCombinationofamantadine,ribavirin,andoseltamivirhasshownadditiveorsynergisticeffectinanimalmodelsndashclinically,arandomizedcontrolledtrialcomparingthetriplecombinationantiviraldrugversusoseltamiviraloneiscurrentlyinprogressAsthenovelclassesofantiviralcompoundsagainstinfluenzabecameavailable,thebenefitofcombinationtherapycanbefurtherevaluatedclinicallyCombinationsbetweenantiviralagentswithimmunemodulatorycompoundshavebeenevaluatedinanimalmodelsandamongpatientswithsevereinfluenzainfectionsThecombinationofoseltamivirwithNacetylcycteineorthesphingosineanalogAALR,zanamivirwiththeCOXinhibitorandmesalazine,orlaninamivirwiththeartificialsurfactanthavebeenshowntoincreasesurvivalinanimalmodelsClinically,systemicglucocorticoidsmaybeusedtoincr

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