6533b86efe1ef96bd12cc925
RESEARCH PRODUCT
Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity
Mark P. Del BorgoIbai E. ValverdeIbai E. ValverdeLinda CerofoliniAlba MascarinHamidreza ShayeAdina T. Michael-titusClaudio LuchinatVadim CherezovFrancesca MagnaniEssam GhazalyPatrick N. PallierMarco FragaiAndreas G. TzakosThomas L. MindtNelofer SyedMarie-isabel AguilarEirinaios I. VrettosNathalie M. GrobEvgenios Κ. StylosTim CrookRobert E WiddopNick BekasEmal WaqifBaydaa HirmizGiacomo Parigisubject
PeptidomimeticStereochemistryChemistry Multidisciplinary[SDV]Life Sciences [q-bio]G-protein-coupled receptorsPeptide[CHIM.THER]Chemical Sciences/Medicinal ChemistryLigandsClick chemistry; Competition-binding experiments; G-protein-coupled receptors; Neurotrophic effects; Peptidomimetics010402 general chemistry01 natural sciencesCatalysisSubstrate Specificityneurotrophic effectscompetition-binding experimentsAnimalsHumansPeptide bondAmino AcidsComputingMilieux_MISCELLANEOUSG protein-coupled receptorchemistry.chemical_classificationReceptors AngiotensinScience & TechnologyAngiotensin II receptor type 1010405 organic chemistry[CHIM.ORGA]Chemical Sciences/Organic chemistryAngiotensin IIOrganic ChemistryGeneral ChemistryAngiotensin II0104 chemical sciencesAmino acidChemistryHEK293 CellschemistrypeptidomimeticsMutationPhysical Sciencesclick chemistryPeptides03 Chemical SciencesTwo-dimensional nuclear magnetic resonance spectroscopydescription
Mutating the side-chains of amino acids in a peptide ligand, with unnatural amino acids, aiming to mitigate its short half-life is an established approach. However, it is hypothesized that mutating specific backbone peptide bonds with bioisosters can be exploited not only to enhance the proteolytic stability of parent peptides, but also to tune its receptor subtype selectivity. Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations. All the analogues possessed enhanced stability in human plasma in comparison with the parent peptide, whereas only two of them achieved enhanced AT2R/AT1R subtype selectivity. This diversification has been studied through 2D NMR spectroscopy and unveiled a putative more structured microenvironment for the two selective ligands accompanied with increased number of NOE cross-peaks. The most potent analogue, compound 2, has been explored regarding its neurotrophic potential and resulted in an enhanced neurite growth with respect to the established agent C21. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. ISSN:0947-6539 ISSN:1521-3765
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-08-21 |