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1、Vol.36,1992POTENTIATORSOFACYCLOVIR937AntimicrobialAgentsandChemotherapy,May1992,p.934-9370066-4804/92/050934-04$02.00/0Copyright©1992,AmericanSocietyforMicrobiologyInactivatorsofHerpesSimplexVirusRibonucleotideReductase:HematologicalProfilesandInVivoPotentiationoftheAntiviralActivityofA
2、cyclovirTHOMASSPECTOR,1*DAVIDC.LOBE,2M.NIXONELLIS,2TODDA.BLUMENKOPF,3andGEORGEM.SZCZECH4DivisionsofExperimentalTherapy,1Virology,2OrganicChemistry,3andToxicologyandPathology,4WellcomeResearchLaboratories,ResearchTrianglePark,NorthCarolina27709Received12November1991/Accepted21January1992
3、A1110U(BW1110U81)isaninactivatorofherpesvirusribonucleotidereductasesandapotentiatoroftheantiviralactivityofacyclovir(ACV)(T.Spector,J.A.Harrington,R.W.Morrison,Jr.,C.U.Lambe,D.J.Nelson,D.R.Averett,K.Biron,andP.A.Furman,Proc.Natl.Acad.Sci.USA86:1051-1055,1989)thatwassubsequentlyfoundtoc
4、ausehematologicaltoxicityathighoraldosesinrats.Elevenstructurallyrelatedinactivatorsofherpessimplexvirus(HSV)ribonucleotidereductasewerethereforetestedinvivoforhematologicaltoxicityandforpotentiationofACV.Noneofthenovelribonucleotidereductaseinactivatorswashematologicallytoxictoratsfoll
5、owingoraldosingat60mg/kg/dayfor30days.FouroftheseinactivatorsstatisticallyimprovedtheantiviraltopicalpotencyofACVonHSVtype1-infectednudemice.Apromisingcompound，2-acetylpyridine5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone(BW348U87),wasstud iedmoreextensivelyintwoinvivomodels:dor
6、sum-infectedathymicnudemiceandsnout-iofectedhairlessmice.BW348U87significantlypotentiatedtheantiviralactivityofACVagainstallvirusstrainstested,i.e.9wild-type(ACV-sensitive)HSVtype1andHSVtype2strainsandthreemutant(ACV-resistant)HSVtype1strains.ThelatterincludedavirusexpressingaDNApolymer
7、aseresistanttoinhibitionbyACVtriphosphate,avirusdeficientinthymidinekinase(theenzymeresponsibleforphosphorylatingACV),andavirusexpressinganalteredthymidinekinase,whichcatalyzesthenormalphosphorylationofthymidinebutnotofACV.BW348U87andACVarecurrentlybeingdevelopedasacombinationt
