title: New insight into the binding mode of peptides at urotensin-II receptor by Trp-constrained analogues of P5U and urantide.
abstract: Urotensin II (U-II) is a disulfide bridged peptide hormone identified as the ligand of a G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have recently identified both a superagonist of human U-II termed P5U (H-Asp-c[Pen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and the compound termed urantide (H-Asp-c[Pen-Phe-D-Trp-Orn-Tyr-Cys]-Val-OH), which is the most potent UT receptor peptide antagonist described to date. In the present study, we have synthesized four analogues of P5U and urantide in which the Trp(7) residue was replaced by the highly constrained L-Tpi and D-Tpi residues. The replacement of the Trp(7) by Tpi led to active analogues. Solution NMR analysis allowed improving the knowledge on conformation-activity relationships previously reported on UT receptor ligands.
authors.affiliation: Department of Pharmacy, University of Naples Federico II, I-80131 Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Luigia
authors.initials: L
authors.lastname: Auriemma
authors.forename: Francesco
authors.initials: F
authors.lastname: Merlino
authors.forename: Antonio
authors.initials: A
authors.lastname: Limatola
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.forename: Roberta d'Emmanuele
authors.initials: Rd
authors.lastname: di Villa Bianca
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Paolo
authors.initials: P
authors.lastname: Santicioli
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
mesh_terms: D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry; D036361:Peptide Hormones / Q000819:agonists / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D014579:Urotensins / Q000138:chemical synthesis* / Q000737:chemistry; D014662:Vasoconstrictor Agents / Q000737:chemistry
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D036361:Peptide Hormones; D010455:Peptides; D010456:Peptides, Cyclic; C479080:UTS2B protein, human; D014579:Urotensins; D014662:Vasoconstrictor Agents; C466635:aspartyl-cyclo(penicillamyl-phenylalanyl-tryptophyl-lysyl-tyrosyl-cysteinyl)valine; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; D014364:Tryptophan