Discovery of Dual-Action Membrane-Anchored Modulators of Incretin Receptors 英文参考文献.docVIP

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Discovery of Dual-Action Membrane-Anchored Modulators of Incretin Receptors 英文参考文献.doc

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Discovery of Dual-Action Membrane-Anchored Modulators of Incretin Receptors 英文参考文献

DiscoveryofDual-ActionMembrane-Anchored ModulatorsofIncretinReceptors Jean-PhilippeFortin1,DanielChinnapen2,MartinBeinborn1,WayneLencer2,AlanS.Kopin1* 1MolecularPharmacologyResearchCenter,MolecularCardiologyResearchInstitute,TuftsMedicalCenter,TuftsUniversitySchoolofMedicine,Boston,Massachusetts, UnitedStatesofAmerica,2GastrointestinalCellBiologyandHarvardDigestiveDiseasesCenter,Children’sHospitalandHarvardMedicalSchool,Boston,Massachusetts, UnitedStatesofAmerica Abstract Background: The glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP-1) receptors are considered complementary therapeutic targets for type 2 diabetes. Using recombinant membrane-tethered ligand (MTL)technology,thepresentstudyfocusedondefiningoptimizedmodulatorsofthesereceptors,aswellasexploringhow localanchoringinfluencessolublepeptidefunction. Methodology/PrincipalFindings:Serialsubstitutionofresidue7inmembrane-tetheredGIP(tGIP)ledtoawiderangeof activitiesattheGIPreceptor,with[G7]tGIPshowingenhancedefficacycomparedtothewildtypeconstruct.Incontrast, introductionofG7intotherelatedligands,tGLP-1andtetheredexendin-4(tEXE4),didnotaffectsignalingatthecognate GLP-1receptor.BothsolubleandtetheredGIPandGLP-1wereselectiveactivatorsoftheirrespectivereceptors.Although solubleEXE4ishighlyselectivefortheGLP-1receptor,unexpectedly,tetheredEXE4wasfoundtobeapotentactivatorof boththeGLP-1andGIPreceptors.DivergingfromthepharmacologicalpropertiesofsolubleandtetheredGIP,thenewly identified GIP-R agonists, (i.e. [G7]tGIP and tEXE4) failed to trigger cognate receptor endocytosis. In an attempt to recapitulatethedualagonismobservedwithtEXE4,weconjugatedsolubleEXE4toalipidmoiety.Notonlydidthissoluble peptideactivateboththeGLP-1andGIPreceptorsbut,whenaddedtoreceptorexpressingcells,theactivitypersistsdespite serialwashes. Conclusions:ThesefindingssuggestthatconversionofarecombinantMTLtoasolublemembraneanchoredequivalent offers a means to prolong ligand function, as well as to design ago