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1、ArchVirol(1997)142:1585±1602Beta-cyclodextrinderivativesascarrierstoenhancetheantiviralactivityofanantisenseoligonucleotidedirectedtowardacoronavirusintergenicconsensussequenceS.Abdou,J.Collomb,F.Sallas,A.Marsura,andC.FinanceGEVSM,EA1123,UniversiteÂHenriPoinc
2、are±Nancy1,FaculteÂdePharmacie,Nancy,FranceAcceptedMarch17,1997Summary.Theabilityofcyclodextrinstoenhancetheantiviralactivityofaphosphodiesteroligodeoxynucleotidehasbeeninvestigated.A18-meroligodeoxynucleotidecomplementarytotheinitiationregionofthemRNAcoding
3、forthespikeproteinandcontainingtheintergenicconsensussequenceofanentericcoronavirushasbeentestedforantiviralactionagainstvirusgrowthinhumanadenocarcinomacells.Thephosphodiesteroligodeoxynucleo-tideonlyshowedalimitedeffectonvirusgrowthrate(from12to34%viralinhi
4、bitionincellstreatedwith7.5to25mMoligodeoxynucleotide,respectively,atamultiplicityofinfectionof0.1infectiousparticlepercell).Inthesameconditions,thephosphorothioateanalogueexhibitedstrongerantiviralactivity,theinhibitionincreasedfrom56to90%.Theinhibitoryeffec
5、tofthisanaloguewasantisenseandsequence-speci®c.Northernblotanalysisshowedthatthesequence-dependentmechanismofactionappearstobetheinhibitionofmRNAtranscription.Weconcludethatthecoronavirusintergenicconsensussequenceisagoodtargetforanantisenseoligonucleotideant
6、iviralaction.Thepropertiesofthephosphodiesteroligonucleotidewasimprovedafteritscomplexationwithcyclodextrins.Themostimportantincreaseoftheantiviralactivity(90%inhibition)wasobtainedwithonly7.5mMoligonucleotidecomplexedtoacyclodextrinderivative,6-deoxy-6-S-b-D
7、-galactopyranosyl-6-thio-cyclomalto-heptaoseinamolarratioof1:100.Thesestudiessuggestthattheuseofcyclodextrinderivativesascarrierforphosphodiesteroligonucleotidesdeliverymaybeaneffectivemethodforincreasingthetherapeuticpotentialofthesecompoundsinviralinfection
8、s.IntroductionTheuseofantisenseoligonucleotidesisaninterestingapproachtostudycellularandviralgenefunctionandtoblockgeneexpression[2,3,60].Oligonucleotideshavebeenconsideredasidealagentsfo
