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1、DOI:10.1002/cbic.200500533AnEfficientMethodfortheSynthesisofPeptideAldehydeLibrariesEmployedintheDiscoveryofReversibleSARSCoronavirusMainproProtease(SARS-CoVM)Inhibitors[a,e][a][a][a,d]SamerI.Al-Gharabli,SyedT.AliShah,SteffenWeik,MarcoF.Schmidt,[b][c][c][b]JeroenR.Mesters,DanielKuhn,GerhardKlebe,Ro
2、lfHilgenfeld,and[a,d]JçrgRademann*proproAmethodfortheparallelsolid-phasesynthesisofpeptidealde-SARS-CoVM(alsoknownas3CL),onthebasisofthreediffer-hydeshasbeendeveloped.Protectedaminoacidaldehydesob-entreportedbindingmodesandsupportedbyvirtualscreening.tainedbytheracemization-freeoxidationofaminoalco
3、holswithAsetof25peptidealdehydeswaspreparedbythismethodandproDess–MartinperiodinanewereimmobilizedonthreonylresinsasinvestigatedininhibitionassaysagainstSARS-CoVM.Severaloxazolidines.FollowingBocprotectionoftheringnitrogentopotentinhibitorswerefoundwithIC50valuesinthelowmicromo-yieldtheN-protectedo
4、xazolidinelinker,peptidesynthesiswaslarrange.AnIC50of7.5mmwasfoundforAcNSTSQ-Handperformedefficientlyonthisresin.ApeptidealdehydelibrarywasAcESTLQ-H.Interestingly,themostpotentinhibitorsseemtobindprodesignedfortargetingtheSARScoronavirusmainprotease,toSARS-CoVMinanoncanonicalbindingmode.Introductio
5、nInNovember2002,anovelmedicalconditionemergedinTheworkpresentedhereconcernsthepreparationandproSouthernChinacharacterizedbysymptomsoffever,chills,ma-identificationofreversibleSARS-CoVMinhibitors.Peptideal-laise,headache,cough,anddyspnea,withradiologicalevi-dehydeshavebeenestablishedasinhibitorsofse
6、veralclasses[11][12,13]denceofpneumonia.Thediseasewasnamedsevereacuteres-ofproteolyticenzymesincludingasparticproteases,cys-[14,15][16,17]piratorysyndrome(SARS),andanovelcoronavirus,SARS-CoV,teineproteases,andserineproteases.Despitetheirre-[1–4]wasidentifiedasitscausativeagent.Althoughtheprimaryact
7、ivityaselectrophiles,atherapeuticpotentialhasalsobeen[18]SARSepidemicwascontrolledbythesummerof2003—afterattributedtopeptidealdehydes.Moreover,peptidealde-affectingabout8500patientsandleaving800dead—there-h
