09-病毒学virus巴斯德研究所

Anti-viraldrugtherapyIPSTetsuyaToyodaMarch21,2006TheNobelPrizeinPhysiologyorMedicine1988fortheirdiscoveriesofimportantprinciplesfordrugtreatmentSirJamesW.Black1924-,UKGertrudeB.Elion1918-1999,USAGeorgeH.Hitchings1905-1998,USAlymphocytebrainheartlungkidneyspleenintestineInfectedmonocytePrimaryviremiaSecondaryviremiaSubcutanealhaemangitisSkinrushFreevirionsLocallymphnodeantibodiesSystemiclymphnodesSSPEvirusDropletinfectionKoplikspotLocalinfectionSystemicinfectionlypmocytepeniaVirusreplicationinvivoMeaslesviruslymphocytebrainheartlungkidneyspleenintestineInfectedmonocytePrimaryviremiaSecondaryviremiaSubcutanealhaemangitisSkinrushFreevirionsLocallymphnodeantibodiesSystemiclymphnodesSSPEvirusDropletinfectionKoplikspotLocalinfectionSystemicinfectionlypmocytepeniaHostdefenseMeaslesvirussIgAIFN(innate)IgG(acquired)CTL(CD8)12345678910111213141516171819200EnteringinrespiratoryrouteReplicationinthelocallymphatictissuesSpreadfromthelocalepitheliaCatarrhconjunctivitisKoplicspotrashantibodies(IgG)VirusreplicationClinicalsymptomsDateafterinfectionSystemicinfectionLocalinfectionacutedisseminatedencephalomyelitis(ADEM)CourseofvirusinfectionAcyclovirBeforeAcyclovirAfteracyclovirdeathcuretreatViralspecificstep1.Interferona,b2.Antivirals3.siRNA(antisenceoligonucleotides)SiRNA(RNA-inducedsilencingcomplexes)mRNANS1PB1-F2adsorptionParentvirusendocytosisMembranefusionendosomeuncoatingnucleusHA、NA、M2Transcription,replicationtranslationM1、NS2buddingreleaseNewvirusReplicationofInfluenzaVirusendocytosisMembranefusionuncoatingbuddingreleaseNP,RdRpendosomeHA、NA、M2adsorptionNewvirusnucleusM1、NS2mRNATranscription,replicationtranslationNS1PB1-F2vaccineNeuraminidaseinhibitorParentvirusamantadineAnti-InfluenzaDrugsIdeaforanti-viraldrugdevelopment1.Viralspecificmetabolism:AcyclovirNobelprizein1988Elion,HictchingandBlack2.Moleculardesignfromternarystructureofviralproteins:ZanamivirvonItzsteinetal.Nature363:418-231993.Anti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseAnti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseViralenzymesInhibitorsAntagonistsAnti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseNucleotideanalogHSVreplicationHSVHerpesvirusTKGuanineacyclovirCellularkinaseHerpesvirusDNApolActionofacyclovirAcycloGMPAcycloGTPHSV5’3’Chainterminator1HSV5’3’Chainterminator2HSVhepadnavirallifecycleHBVHBVpolinhibitorlamivudinetriphosphateHBVHIVreplicationRTintegrationprocessingprocessingHIVnonnucleotideRTinhibitors(NNRTI)HIV-1withNNRTIHIVHIVRTmutationHIVAnti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseHIV-1proteaseindinavirHIVHIVmutationfromproteaseinhibitorsAnti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseFluAM2ionchannelFluPinto&Lamb,JBiolChem.2005FluPinto&Lamb,JBiolChem.2005FluAM2,FluBM2FluAmantadinestucksinM2FluHayetal.EMBOJ.4:3021-3024,1985AminoacidmutationofADresistantM2Hayetal.EMBOJ.4:3021-3024,1985AminoacidmutationofADresistantM22FluAnti-viraldrugs1.Anti-viralpolymerase2.Anti-viralprotease3.Anti-viralionchannel4.Anti-viralneuraminidase5.Anti-viralintegraseoseltamivirRelenzaTamifluTheactivesiteofinfluenzaAneuraminidaseFluStructureofGG167(Zanamivir)FluCombinationofanti-virals1.HIV:HAART2.HCV:interferon+ribavirinTargetsofantiretroviraltherapyHighlyActiveAnti-RetroviralTherapy(HAART)Antiretroviralregimens2nucleosidereversetranscriptaseinhibitors,eg,zidovudineorstavudine+lamivudineordidanosinePluseither1non-nucleosidereversetranscriptaseinhibitor:nevirapineorefavirenzor1proteaseinhibitor:indinavir,nelfinavirorsaquinavirsoftgelor2proteaseinhibitors,eg,ritonavir+saquinavir3nucleosidereversetranscriptaseinhibitors:zidovudine+lamivudine+abacavirRecommendedantiretroviralregimensfortheinitialtreatmentofchronicinfectioninadults(2001).Choicewilldependonefficacy,tolerability,adherence,andresistanceprofileofregimen.Treatmentguidelinesareconstantlyreviewedandupdated.Kaufmannetal.SexTransmInf1999;75:218–224HIV’ssarcoma(KS)primarycentralnervoussystemlymphoma(PCNSL)AIDS-relatednon-Hodgkin’slymphoma(ARL)Non-AIDS-definingmalignanciesHIV-relatedHodgkin’sLymphoma(HL)multiplemyeloma(MM)AIDS-definingmalignanciesHIVHCVgenomestructuresHCVSmith,R.M.&Wu,G.Y.JournalofViralHepatitis10(6),405-412.HCVinhibitorsPolymeraseinhibitorsNS3proteaseinhibitors