新型抗HIV药物靶点核糖核酸酶H抑制剂的研究进展

JournalofChinaPharmaceuticalUniversity2011426578－584··HIVH112*112300162HIVHIV。HIV。HHIV。HH。HHIVQ55A1000－5048201106－0578－07AdvancesinthestudyoninhibitorsofRNaseH，anovelanti-HIVdrugtargetDENGLian-bai1，LIAi-xiu1，2*，JINYu-rui11DrugDesignLaboratoryoftheBasicScienceDepartment;2TianjinKeyLaboratoryforBiomarkersofOccupationalandEnvironmentalHazard，LogisticsUniversityofChinesePeoplesArmedPoliceForce，Tianjin300162，ChinaAbstractAstheinfectionoftheacquiredimmunodeficiencysyndrome(AIDS)andthemutationoftheHIVviruskeepincreasing，theresanurgentdemandfordevelopingnewanti-HIVdrugs.Uptillnow，theresearchonanti-HIVagentshasbeencarriedoutintwoways:basedonknowntargetsornewtargets.RibonucleaseH(RNaseH)，whichhaswithitsownuniquecatalyticsitesofenzymefunctionandisregardedasanoveldrugtargetforanti-HIVtherapy，isadomainofthereversetranscriptase.ThisreviewsummarizesRNaseHinhibitorsdiscoveredinrecentyearsandexplainstheirmechanismsofactionwhichaimsatprovidingsomeusefulinformationforfurtherstructuralmodificationsanddesignofRNaseHinhibitors.Keywordsreversetranscriptase(RT);RNaseH;anti-HIV;chemicalsynthesis;plantextracts;inhibitors;advancesThisstudywassupportedbythetheNationalNaturalScienceFoundationofChina(No.30472166);theTianjinCommissionofSci-enceandTechnology(No.06YFGZSH07000);theCollegeFoundationofMedicalCollegeofChinesePeoplesArmedPoliceForce(No.WYD200901)acquiredimmunod-eficiencysyndromeAIDS。198511002。humanimmunodeficiencyvirusHIVHIVHIV-1HIV-2HIV-1HIV。HIV-1、、、4。875*2011-07-20*[e-mail]2009016HIVH。HIV。HIV-1HRibonucleaseHRNaseHRNaseHRNaseH。1RNaseHHIV-1HIV-1reversetranscriptaseHIV-1RTp66p51。p51440p66RNaseHp66p51p66。p66、、、RNaseH1。RNADNADNADNARNaseH。RNaseH。RNaseHp66p66Tyr427Leu5602。XHIV-1RNaseHRNaseH4α5βαβ3。RNaseHRNaseHRNaseH。RNaseHHIVRNADNA3①DNARNaseHRNADNA②③DNAtRNA4－5。RNaseHRNADNARNA3'5'。Schultz65'5'、5'。RNaseHHIVRNaseH。2RNaseHRNaseH205-、、N-N-。12RNaseH7。RNaseHRNaseH。RNaseH、。2.15-RNaseHMg2+Mg2+3.71。5-37-。37-RNaseH、3'。121237-。8。Figure1BindmodeofinhibitorandMg2+blackdotinthepicture2.2N-N-5-。N-34.02.12。RNaseH。N-RNaseH1HIVRNaseH9。Figure2BindmodeofN-hydroxyimides2.3/HIV-1RNaseH975JournalofChinaPharmaceuticalUniversity42RNaseH10。4-5--2--24-BTDBAIC503.2～4.7μmol/LRNADNARNaseHHIV-1RNaseH11。20056-1-4--1H--2--24--5-RDS1643RNaseHDNA、RNaseH。RDS1643IC5013μmol/LHIV-1EC5014μmol/L4。NNRTIRDS1643HIV-1。RDS1643、12。2.4N-N-RNaseHN-4--2--1-BBNHRNaseH。Sluis-Cremer13BBNH4--2--1-BBSHRTBBSHBBNHDNARNaseH。BBNHBBSH。BBNHRNaseHTyr501Tyr501Tyr501BBNHTyr501RNaseH。BBNHN-。2007Himmel14N-———34--N-2-1-DHBNHDHBNHBBNHDHBNHRNaseH50。DHBNH“”DHBNHRNaseHNNRT。“”NNRTI“”。DHBNH“”。2.5RNaseHBTDBA、N-、β-thujaplicinol3。Kirschberg1533、45RNaseH。。His539。6HIV-1HIC500.18μmol/L。0856HIVH2.62010Williams16HIV-1RNaseH。14--18--21H--3-7。7RNaseH。73。74、、8RNaseHIC50=0.045μmol/L。8RNaseH290530。84。8IC50。Figure3Crystalstructureofcompound7withfullRT172.75--2-20000Hiroshi1820115--2-9RNaseH。--RNaseHR。-3。。2.8、、。3RNaseH、、。RNaseHIllimaquinoneSmenospongiasp19。IllimaquinoneRNaseH5～10μg/mLIllimaquinone10μg/mLRNaseH62%。RNaseHIC50140μmol/LRNaseHIC5015μmol/L。Loya20Illimaquinone6'OHRNaseH。RNaseHIllimaquinone。3.1β-thujaplicinolmanicolRNaseH。β-thujaplicinolHIV-1HIV-2RNaseHHIV-1IC500.2μmol/L。β-thujaplicinol7OHββαγα-thuja-plicinγ-thujaplicinHIV-1RNaseH。7OHmanicolHIV-1IC50401.5μmol/L21。、、。β-thujaplicinolNNRTIcalanol-ideA185JournalofChinaPharmaceuticalUniversity42NNRT。3.2Eugeniahyemalis22、Ardisiajaponica23、Hylodendrongabunensis24RNaseH。。ArdisiajaponicaArdisiajaponica76RNaseH。ArdimerindigallateHIV-1HIV-2RNaseHIC501.51.1μmol/LArdimerindigallate200μmol/LRNaseH。Ardimerindigallate23。Hylodendrongabunensis1345-Tetragalloylapiitol4HIV-1HIV-2RNaseHIC500.240.13μmol/LRNaseHIC501.5μmol/L10μmol/L24。1345-Tetragalloylapiitol。3.3HIV-1。RNaseH2009Tatyana25RNaseH。7RNaseH67--6---18--3-IC50=14μmol/LRNaseH2.5NNRTI。3.4HIV。Juglansmandshurica、Dysideacinerea、DryopteriscrassirhizomaRNaseHRNaseH。4RNaseH。Hannoush26RNA。HIV-1RNaseH2856HIVH。2'5'-UUCG2'5'-UACG。643。UUCGUUCGIC50=3.3μmol/L1011。5HIV-1。。RNaseH2027、、28。RNaseH。RNaseH。-RNaseH。DHBNH“”“”。RNaseHRNaseH。DNA29－31RNaseH。1HuangHChopraRVerdineGLetal．StructureofacovalentlytrappedcatalyticcomplexofHIV-1reversetranscriptaseimplica-tionsfordrugresistanceJ．Science199828253941669－1675.2DaviesJFHostomskaZHostomskyZetal．CrystalstructureoftheribonucleaseHdomainofHIV-1reversetranscriptaseJ．Science1991252500288－95.3PariKMuellerGADeRoseEFetal．SolutionstructureoftheRNaseHdomainoftheHIV-1reversetranscriptaseinthepres-enceofmagnesiumJ．Biochemistry2003423639－650.4ArtsEJLeGriceSF．Interactionofretroviralreversetranscriptasewithtemplate-primerduplexesduringreplicationJ．ProgNucle-icAcidResMolBiol199858339－393.5RauschJWLeGriceSF．‘Bindingbendingandbonding’poly-purinetract-primedinitiationofplus-strandDNAsynthesisinhumanimmunodeficiencyvirusJ．IntJBiochemCellBiol20043691752－1766.6SchultzSJZhangMHChampouxJJ．Sequencedistanceandaccessibilityaredeterminantsof5'-end-directedcleavagesbyretroviralRNasesHJ．JBiolChem200628141943－1955.7YuFLiuXY．HIV-1HJ．ChinPharmJ2007427481－486.8D