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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-CoVinfectedVeroE6cellsandbroadenedspeci?citytowardthehomologousPLP2enzymefromthehumancoronavirusNL63.Selectivityandcytotoxicitystudiesestablishedamorethan100-foldpreferenceforthecoronaviralenzymeoverhomologoushumandeubiquitinatingenzymes(DUBs),andnosign
5、i?cantcytotoxicityinVeroE6andHEK293celllinesisobserved.X-raystructuralanalysesofinhibitor-boundcrystalstructuresrevealedsubtledi?erencesbetweenbindingmodesoftheinitialbenzodioxolanelead(15g)andthemostpotentanalogues3kand3j,featuringamono?uorosubstitutionatparaandmetapositionsofthebe
6、nzylring,respectively.Finally,thelesslipophilicbis(amide)3eandmethoxypyridine5cexhibitsigni?cantlyimprovedmetabolicstabilityandareviablecandidatesforadvancingtoinvivostudies.■INTRODUCTIONReminiscentoftheinitialstagesofSARS-CoVpandemic,globaltravelhascontributedtothespreadofMERScoron
7、avirus,withMorethan10yearsafterthepandemiccausedbytheSARS6atotalof178laboratory-con?rmedcasesandaCFRof43%.(severeacuterespiratorysyndrome)coronavirus(CoV),noTheinfectedindividualsdisplaySARS-likesymptoms,includinganticoronaviralregimenshavebeendevelopedforthetreatmentasevererespirat
8、oryinfection(SRI),a
