Redox-Based Inactivation of Cysteine Cathepsins by Compounds Containing the 4-Aminophenol Moiety 英文参考文献.docVIP

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Redox-Based Inactivation of Cysteine Cathepsins by Compounds Containing the 4-Aminophenol Moiety 英文参考文献.doc

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Redox-Based Inactivation of Cysteine Cathepsins by Compounds Containing the 4-Aminophenol Moiety 英文参考文献

Redox-BasedInactivationofCysteineCathepsinsby CompoundsContainingthe4-AminophenolMoiety BojanaMirkovic′1*,IzidorSosicˇ2,StanislavGobec2,JankoKos1,3 1Department ofPharmaceuticalBiology,FacultyofPharmacy,UniversityofLjubljana,Ljubljana,Slovenia,2DepartmentofMedicinalChemistry,FacultyofPharmacy, UniversityofLjubljana,Ljubljana,Slovenia,3DepartmentofBiotechnology,Jozˇef StefanInstitute,Ljubljana,Slovenia Abstract Background:Redoxcyclingcompoundshavebeenreportedtocausefalsepositiveinhibitionofproteasesindrugdiscovery studies.Thiskindoffalsepositivescanleadtounusuallyhighhitratesinhigh-throughputscreeningcampaignsandrequire furtheranalysistodistinguishtruefromfalsepositivehits.Suchfollow-upstudiesarebothtimeandresourceconsuming. MethodsandFindings:Inthisstudyweshowthat5-aminoquinoline-8-olisatime-dependentinactivatorofcathepsinB 21 21 withakinact/KIof36.7613.6M sameconcentrationrange,implyinganon-specificmechanismofinhibition.Furtheranalogues,4-aminonaphthalene-1-ol s usingenzymekinetics.5-Aminoquinoline-8-olinhibitedcathepsinsH,LandBinthe and 4-aminophenol, also displayed time-dependent inhibition of cathepsin B with kinact/KI values of 406.4610.8 and 21 21 36.561.3M s .Noinactivationoccurredintheabsenceofeithertheaminoorthehydroxylgroup,suggestingthatthe4- aminophenolmoietyisaprerequisiteforenzymeinactivation.Inductionofredoxoxygenspecies(ROS)by4-aminophenols in various redox environments was determined by the fluorescent probe 29,79-dichlorodihydrofluorescein diacetate. AdditionofcatalasetotheassaybuffersignificantlyabrogatedtheROSsignal,indicatingthatH2O2isacomponentofthe ROSinducedby4-aminophenols.Furthermore,usingmassspectrometry,activesiteprobeDCG-04andisoelectricfocusing we show that redox inactivation of cysteine cathepsins by 5-aminoquinoline-8-ol is active site directed and leads to the formationofsulfinicacid. Conclusions:Inthisstudywereportthatcompoundscontainingthe4-aminophenolmoietyinactivatecysteinecathepsins through a redox-based mechanism and are t