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1、PerspectivesinDrugDiscoveryandDesign,1(1993)211-224211ESCOMPD3009Iminosugarglycosylationinhibitorsasanti-HIVagentsGaryS.Jacoba'*andMartinL.BryantbaGlycosciencesUnit,MonsantoCorporateResearch,800NorthLindberghBlvd.,St.Louis,MO63167,U.S.A.bInfectiousDiseaseResearch,G.
2、D.Searle,700ChesterfieldVillageParkway,St.Louis,MO63198,U.S.A.Received17February1993Accepted9June1993Keywords."N-butyt-deoxynojirimycin;cx-Glucosidaseinhibitors;Anti-HIVprodrugSUMMARYAnovelclassofcompoundswhicharepotentinhibitorsoftheposttranslationalglycantrimminge
3、nzymea-glucosidaseIhavebeenfoundtodisplayanti-HIVactivity.ThesecompoundsareiminosugaranalogsofD-glucose,withtheoxygenintheringreplacedbyanitrogen,andwereoriginallyisolatedfromplantsandmicroorganisms,althoughaconsiderablenumberofanalogshavebeensynthesizedduringthepas
4、tfewyears.Oneofthesecompounds,N-butyl-l-deoxynojirimycin(Bu-DNJ),ispresentlyunderevaluationinclinicaltrialsforthecontrolofHIVinfections.Cumulativedata,todate,suggestthatcompoundssuchasN-Bu-DNJhaveahierarchyofeffects,withreductioninsyncytiaformationbeingthepredominan
5、tfeature,andareknowntoalterglycosylationoftheHIV-1envelopeglycoproteinsgp120andgp41.Consequently,thereareanumberofdifferentwaysinwhichiminosugarsmaybeexertinganantiviraleffect.Thispaperdiscussesthebasicpropertiesofthisclassofcompoundsandthechangestheyeffectinposttra
6、nslationalprocessingofgp120andgp41,aswellasthesynthesisandcharacterizationofprodrugformsofBu-DNJ(e.g.N-butyl-6-phospho-l-deoxynojirimycin),whichdonotinhibitintestinaldisaccharidasesandmaybeusefulforeliminatingtheintestinaldiscomfortanddiarrheaassociatedwithadministr
7、ationofa-glucosidaseinhibi-tors.INTRODUCTIONAnearlyapproachtothestudyofthestructuralandfunctionalroleofglycosylationwastoidentifyandusespecificinhibitorsoftheenzymesinvolvedintheglycosylationprocessingpath-way.Inthiswaythestepwisemodelingoftheseglycanscouldbeexplore
8、dandthecontributionofglycosylationtotheoverallfunctionofglycoproteinscouldbestudied.Inhibitorsofexoglyco-sidaseswereinitiallydiscoveredasn
