Design of a Highly Selective Quenched Activity-Based Probe部分

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1、Articlepubs.acs.org/JACSDesignofaHighlySelectiveQuenchedActivity-BasedProbeandItsApplicationinDualColorImagingStudiesofCathepsinSActivityLocalization††††∥KristinaOresicBender,LeslieOfori,WouterA.vanderLinden,ElliotD.Mock,GopalK.Datta,∥§††∥,#SomenathChowdhury,HaoLi,

2、EhudSegal,MateoSanchezLopez,JonathanA.Ellman,⊥,†,‡,§,†,⊥CarlG.Figdor,MatthewBogyo,*andMartijnVerdoes*†‡§DepartmentsofPathology,MicrobiologyandImmunology,andChemicalandSystemsBiology,StanfordUniversitySchoolofMedicine,Stanford,California94305,UnitedStates∥Department

3、ofChemistry,UniversityofCalifornia-Berkeley,Berkeley,California94720,UnitedStates⊥DepartmentofTumorImmunology,RadboudUniversityMedicalCenter,RadboudInstituteforMolecularLifeSciences,6500HBNijmegen,TheNetherlands*SSupportingInformationABSTRACT:Thecysteinecathepsinsa

4、reagroupof11proteaseswhosefunctionwasoriginallybelievedtobethedegradationofendocytosedmaterialwithahighdegreeofredundancy.However,ithasbecomeclearthattheseenzymesarealsoimportantregulatorsofbothhealthanddisease.Thus,selectivetoolsthatcandiscriminatebetweenmembersof

5、thishighlyrelatedclassofenzymeswillbecriticaltofurtherdelineatetheuniquebiologicalfunctionsofindividualcathepsins.Herewepresentthedesignandsynthesisofanear-infraredquenchedactivity-basedprobe(qABP)thatselectivelytargetscathepsinSwhichishighlyexpressedinimmunecells.

6、Importantly,thishighdegreeofselectivityisretainedbothinvitroandinvivo.Incombinationwithanewgreen-fluorescentpan-reactivecysteinecathepsinqABPweperformeddualcolorlabelingstudiesinbonemarrow-derivedimmunecellsandidentifiedvesiclescontainingexclusivelycathepsinSactivity

7、.ThisobservationdemonstratesthevalueofourcomplementarycathepsinprobesandprovidesevidencefortheexistenceofspecificlocalizationofcathepsinSactivityindendriticcells.5■INTRODUCTIONsuchasintestinalepithelialcells.Althoughprimarilylocalizedtotheendolysomalsystem,cathepsin

8、ShasbeenlinkedtoCysteinecathepsinsarepartoftheC1afamilyofclanCA1functionsoutsidethecell,whereitcontributestomatrixproteases.Theseincludecathepsin