冠状病毒Coronavirusl论文-2005 A New Lead for Nonpeptidic Active-Site-Directed Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus Mai.pdf

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1、6832J.Med.Chem.2005,48,6832-6842ANewLeadforNonpeptidicActive-Site-DirectedInhibitorsoftheSevereAcuteRespiratorySyndromeCoronavirusMainProteaseDiscoveredbyaCombinationofScreeningandDockingMethods

2、UlrichKaeppler,²NikolausStiefl,²MarkusSchiller,²RadimVicik,²AlexanderBreuning,²WernerSchmitz,³Dan

3、ielRupprecht,§CarstenSchmuck,§KnutBaumann,²JohnZiebuhr,#andTanjaSchirmeister*,²InstituteofPharmacyandFoodChemistry,UniversityofWuÈrzburg,AmHubland,D-97074WuÈrzburg,Germany,DepartmentofPhysiologicalChemistryII,Theodor-Boveri-Institute,UniversityofWuÈrzburg,AmHubland,D-97074WuÈrzburg,Germany,I

4、nstituteofOrganicChemistry,UniversityofWuÈrzburg,AmHubland,D-97074WuÈrzburg,Germany,andInstituteofVirologyandImmunology,UniversityofWuÈrzburg,VersbacherStrasse7,D-97078WuÈrzburg,GermanyReceivedFebruary24,2005Thecoronavirusmainprotease,Mpro,isconsideredtobeamajortargetfordrugssuitableforcomba

5、tingcoronavirusinfectionsincludingsevereacuterespiratorysyndrome(SARS).AnHPLC-basedscreeningofelectrophiliccompoundsthatwasperformedtoidentifypotentialMproinhibitorsrevealedetacrynicacidtert-butylamide(6a)asaneffectivenonpeptidicinhibitor.Dockingstudiessuggestedabindingmodeinwhichthephenylri

6、ngactsasaspacerbridgingtheinhibitor'sactivateddoublebondanditshydrophobictert-butylmoiety.ThelatterissupposedtofitintotheS4pocketofthetargetprotease.Furthermore,thesestudiesrevealedetacrynicacidamide(6b)asapromisingleadfornonpeptidicactive-site-directedMproinhibitors.Inafluorimetricenzymeass

7、ayusinganovelfluorescenceresonanceenergytransfer(FRET)pairlabeledsubstrate,compound6bshowedaKivalueof35.3íM.SincethenovelleadcompounddoesnottargettheS1¢,S1,andS2subsitesoftheenzyme'ssubstrate-bindingpockets,thereisroomforimprovementthatunderlinestheleadcharacterofcompound6b.Introductionattra

8、ctivetargetfornewantiviraldrugsagainstSARSandothercoronavirusinfections.12CoronavirusesareimportantpathogensthatmainlyAnumberofpotentialinhibitorshavebeenproposedcauserespiratoryandentericdiseaseinhumans,live-1employingmolecularmodelingandvirtualsc