冠狀病毒Coronavirusl論文-2004 Identification of Novel Inhibitors of the SARS Coronavirus Main Protease 3CL_ _sup_pro__sup__sup____su.pdf

冠狀病毒Coronavirusl論文-2004 Identification of Novel Inhibitors of the SARS Coronavirus Main Protease 3CL_ _sup_pro__sup__sup____su.pdf

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1、4906Biochemistry2004,43,4906-4912IdentificationofNovelInhibitorsoftheSARSCoronavirusMainProtease3CLpro2UsmanBacha,3JenniferBarrila,3AdrianVelazquez-Campoy,StephanieA.Leavitt,andErnestoFreire*DepartmentofBiology,JohnsHopkinsUniVersity,Baltimore,Maryland21218ReceiVedDecember3,2003

2、;ReVisedManuscriptReceiVedMarch11,2004ABSTRACT:SARS(severeacuterespiratorysyndrome)iscausedbyanewlydiscoveredcoronavirus.Akeyenzymeforthematurationofthisvirusand,therefore,atargetfordrugdevelopmentisthemainprotease3CLpro(alsotermedSARS-CoV3CLpro).WehaveclonedandexpressedinEscher

3、ichiacolithefull-lengthSARS-CoV3CLproaswellasatruncatedformcontainingonlythecatalyticdomains.Therecombinantproteinshavebeencharacterizedenzymaticallyusingafluorescentlylabeledsubstrate;theirstructuralstabilityinsolutionhasbeendeterminedbydifferentialscanningcalorimetry,andnoveli

4、nhibitorshavebeendiscovered.ExpressionofthecatalyticregionaloneyieldsaproteinwithareducedcatalyticefficiencyconsistentwiththeproposedregulatoryroleoftheR-helicaldomain.DifferentialscanningcalorimetryindicatesthattheR-helicaldomaindoesnotcontributetothestructuralstabilityofthecat

5、alyticdomains.Analysisoftheactivesitecavityrevealsthepresenceofsubsitesthatcanbetargetedwithspecificchemicalfunctionalities.Inparticular,aclusterofserineresidues(Ser139,Ser144,andSer147)wasidentifiedneartheactivesitecavityandwassusceptibletobeingtargetedbycompoundscontainingboro

6、nicacid.Thisclusterishighlyconservedinsimilarproteasesfromothercoronaviruses,defininganattractivetargetfordrugdevelopment.Itwasfoundthatbifunctionalarylboronicacidcompoundswereparticularlyeffectiveatinhibitingtheprotease,withinhibitionconstantsasstrongas40nM.Isothermaltitrationm

7、icrocalorimetricexperimentsindicatethattheseinhibitorsbindreversiblyto3CLproinanenthalpicallyfavorablefashion,implyingthattheyestablishstronginteractionswiththeproteasemolecule,thusdefiningattractivemolecularscaffoldsforfurtheroptimization.FromNovember2002throughJune2003,moretha

8、n8000personscontractedsevereacuterespiratorysyn

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