TY - JOUR
T1 - Single Peptide Backbone Surrogate Mutations to Regulate Angiotensin GPCR Subtype Selectivity
AU - Vrettos, Eirinaios I.
AU - Valverde, Ibai E.
AU - Mascarin, Alba
AU - Pallier, Patrick N.
AU - Cerofolini, Linda
AU - Fragai, Marco
AU - Parigi, Giacomo
AU - Hirmiz, Baydaa
AU - Bekas, Nick
AU - Grob, Nathalie M.
AU - Stylos, Evgenios
AU - Shaye, Hamidreza
AU - Del Borgo, Mark
AU - Aguilar, Marie-Isabel
AU - Magnani, Francesca
AU - Syed, Nelofer
AU - Crook, Timothy
AU - Waqif, Emal
AU - Ghazaly, Essam
AU - Cherezov, Vadim
AU - Widdop, Robert E.
AU - Luchinat, Claudio
AU - Michael-Titus, Adina T.
AU - Mindt, Thomas L.
AU - Tzakos, Andreas G.
PY - 2020/8/21
Y1 - 2020/8/21
N2 - 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 Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations.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.
AB - 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 Towards this end, four [Y]6-Angiotensin II analogues are synthesized where amide bonds have been replaced by 1,4-disubstituted 1,2,3-triazole isosteres in four different backbone locations.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.
KW - click chemistry
KW - competition-binding experiments
KW - G-protein-coupled receptors
KW - neurotrophic effects
KW - peptidomimetics
UR - http://www.scopus.com/inward/record.url?scp=85088233580&partnerID=8YFLogxK
U2 - 10.1002/chem.202000924
DO - 10.1002/chem.202000924
M3 - Article
AN - SCOPUS:85088233580
VL - 26
SP - 10690
EP - 10694
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 1521-3765
IS - 47
ER -