Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity

Eirinaios I. Vrettos, Ibai E. Valverde, Alba Mascarin, Patrick N. Pallier, Linda Cerofolini, Marco Fragai, Giacomo Parigi, Baydaa Hirmiz, Nick Bekas, Nathalie M. Grob, Evgenios Stylos, Hamidreza Shaye, Mark Del Borgo, Marie-Isabel Aguilar, Francesca Magnani, Nelofer Syed, Timothy Crook, Emal Waqif, Essam Ghazaly, Vadim CherezovRobert E. Widdop, Claudio Luchinat, Adina T. Michael-Titus, Thomas L. Mindt, Andreas G. Tzakos

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)


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 Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations.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.

Original languageEnglish
Pages (from-to)10690-10694
Number of pages5
JournalChemistry - A European Journal
Issue number47
Publication statusPublished - 21 Aug 2020


  • click chemistry
  • competition-binding experiments
  • G-protein-coupled receptors
  • neurotrophic effects
  • peptidomimetics

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