Urotensin-II peptidomimetic incorporating a non-reducible 1,5-triazole disulfide bond reveals a pseudo-irreversible covalent binding mechanism to the urotensin G-protein coupled receptor

Organic & Biomolecular Chemistry
Salvatore PacificoAndrew G Jamieson

Abstract

The urotensin-II receptor (UTR) is a class A GPCR that predominantly binds to the pleiotropic cyclic peptide urotensin-II (U-II). U-II is constrained by a disulfide bridge that induces a β-turn structure and binds pseudo-irreversibly to UTR and is believed to result in a structural rearrangement of the receptor. However, it is not well understood how U-II binds pseudo-irreversibly and the nature of the reorganization of the receptor that results in G-protein activation. Here we describe a series of U-II peptidomimetics incorporating a non-reducible disulfide bond structural surrogate to investigate the feasibility that native U-II binds to the G protein-coupled receptor through disulfide bond shuffling as a mechanism of covalent interaction. Disubstituted 1,2,3-triazoles were designed with the aid of computational modeling as a non-reducible mimic of the disulfide bridge (Cys5-Cys10) in U-II. Solid phase synthesis using CuAAC or RuAAC as the key macrocyclisation step provided four analogues of U-II(4-11) incorporating either a 1,5-triazole bridge (5, 6) or 1,4-triazole bridge (9, 10). Biological evaluation of compounds 5, 6, 9 and 10 was achieved using in vitro [125I]UII binding and [Ca2+]i assays at recombinant human UTR. Comp...Continue Reading

References

Jul 4, 1998·The Journal of Biological Chemistry·T H JiI Ji
Nov 5, 2002·Bioorganic & Medicinal Chemistry·Paolo GriecoPaolo Rovero
Jun 17, 2003·The Journal of Pharmacology and Experimental Therapeutics·Alexandre BrkovicAlain Fournier
Aug 29, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Patricia LabarrèreHubert Vaudry
Oct 11, 2003·Biochemical and Biophysical Research Communications·Tsukasa SugoMasahiko Fujino
Dec 4, 2003·British Journal of Pharmacology·Riccardo PatacchiniCarlo Alberto Maggi
Jun 20, 2006·British Journal of Pharmacology·Yi-Chun ZhuPhilip Keith Moore
Apr 3, 2008·Nature Reviews. Drug Discovery·Malin C Lagerström, Helgi B Schiöth
Aug 3, 2010·ACS Medicinal Chemistry Letters·Tiffany S HanGrzegorz Bulaj
Dec 2, 2010·Journal of Medicinal Chemistry·Markus MuttenthalerPaul F Alewood
Aug 4, 2011·Frontiers in Pharmacology·Philip TsoukasAdel Giaid
Sep 26, 2012·Methods in Molecular Biology·Anish PatelDavid G Lambert
Dec 15, 2012·Nature Reviews. Drug Discovery·Raymond C StevensKurt Wüthrich
Aug 21, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Huiyuan LiIrwin Chaiken
Jan 15, 2014·Nature·Gustavo FenaltiRaymond C Stevens
Aug 2, 2014·Asian Journal of Andrology·Roberta d'Emmanuele di Villa BiancaRaffaella Sorrentino
Feb 20, 2015·Journal of Peptide Science : an Official Publication of the European Peptide Society·Diego BrancaccioAlfonso Carotenuto
Mar 4, 2015·Organic & Biomolecular Chemistry·Geoffrey M WilliamsMargaret A Brimble
Dec 15, 2015·ACS Combinatorial Science·Vida CastroFernando Albericio

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Citations

Feb 27, 2020·Organic & Biomolecular Chemistry·Anna Said StålsmedenNina Kann
Jun 16, 2021·European Journal of Medicinal Chemistry·Lucia De RosaLuca Domenico D'Andrea
Aug 28, 2021·RSC Medicinal Chemistry·Clément Bechtler, Christina Lamers

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