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1、Articlepubs.acs.org/jmcX‑rayStructuralandBiologicalEvaluationofaSeriesofPotentandHighlySelectiveInhibitorsofHumanCoronavirusPapain-likeProteases†‡‡‡§YahiraM.Baez-Santos,́ScottJ.Barraza,MichaelW.Wilson,MichaelP.Agius,AnnaM.Mielech,†§,‡,†NicoleM.Davis,SusanC.Baker,ScottD.Larsen,*andAn
2、drewD.Mesecar*†DepartmentofBiologicalSciences,PurdueUniversity,915W.StateStreet,WestLafayette,Indiana47907,UnitedStates‡VahlteichMedicinalChemistryCoreandDepartmentofMedicinalChemistry,CollegeofPharmacy,UniversityofMichigan,AnnArbor,Michigan48109,UnitedStates§DepartmentofMicrobiolog
3、yandImmunology,LoyolaUniversityChicagoStritchSchoolofMedicine,Maywood,Illinois60153,UnitedStatesABSTRACT:Structure-guideddesignwasusedtogenerateaseriesofnoncovalentinhibitorswithnanomolarpotencyagainstthepapain-likeprotease(PLpro)fromtheSARScoronavirus(CoV).Anumberofinhibitorsexhibi
4、tantiviralactivityagainstSARS-CoVinfectedVeroE6cellsandbroadenedspecificitytowardthehomologousPLP2enzymefromthehumancoronavirusNL63.Selectivityandcytotoxicitystudiesestablishedamorethan100-foldpreferenceforthecoronaviralenzymeoverhomologoushumandeubiquitinatingenzymes(DUBs),andnosign
5、ificantcytotoxicityinVeroE6andHEK293celllinesisobserved.X-raystructuralanalysesofinhibitor-boundcrystalstructuresrevealedsubtledifferencesbetweenbindingmodesoftheinitialbenzodioxolanelead(15g)andthemostpotentanalogues3kand3j,featuringamonofluorosubstitutionatparaandmetapositionsofthebe
6、nzylring,respectively.Finally,thelesslipophilicbis(amide)3eandmethoxypyridine5cexhibitsignificantlyimprovedmetabolicstabilityandareviablecandidatesforadvancingtoinvivostudies.■INTRODUCTIONReminiscentoftheinitialstagesofSARS-CoVpandemic,globaltravelhascontributedtothespreadofMERScoron
7、avirus,withMorethan10yearsafterthepandemiccausedbytheSARS6atotalof178laboratory-confirmedcasesandaCFRof43%.(severeacuterespiratorysyndrome)coronavirus(CoV),noTheinfectedindividualsdisplaySARS-likesymptoms,includinganticoronaviralregimenshavebeendevelopedforthetreatmentasevererespirat
8、oryinfection(SRI),a
