Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity.
Fiche publication
Date publication
mai 2020
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr VALVERDE Ibai
Tous les auteurs :
Vrettos EI, Valverde IE, Mascarin A, Pallier PN, Cerofolini L, Fragai M, Parigi G, Hirmiz B, Bekas N, Grob NM, Stylos EΚ, Shaye H, Del Borgo M, Aguilar MI, Magnani F, Syed N, Crook T, Waqif E, Ghazaly E, Cherezov V, Widdop RE, Luchinat C, Michael-Titus AT, Mindt TL, Tzakos AG
Lien Pubmed
Résumé
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 Towards this end, four [Y] -Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations.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 AT R/AT R 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.
Mots clés
G-protein-coupled receptors, click chemistry, competition-binding experiments, neurotrophic effects, peptidomimetics
Référence
Chemistry. 2020 May 4;: