New insight into the binding mode of peptide ligands at Urotensin-II receptor: structure-activity relationships study on P5U and urantide.
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 hU-II termed P5U (H-Asp-c[Pen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and the compound termed urantide (H-Asp-c[Pen-Phe-DTrp-Orn-Tyr-Cys]-Val-OH), which is the most potent UT receptor peptide antagonist described to date. In the present study, we have synthesized several analogues of P5U and urantide in which the Asp(4) residue in N-terminus position was replaced with coded and noncoded amino acids. The replacement of the Asp(4) residue by Tic led to an analogue, compound 14, more potent as antagonist (pK(B) = 8.94) compared to urantide. Furthermore, a different SAR was observed for the P5U compared to the urantide analogues. NMR and docking studies revealed a different binding mode for the agonist and antagonist ligands which could explain the observed SAR.
Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, I-80131 Naples, Italy.
Paolo
P
Grieco
Alfonso
A
Carotenuto
Pietro
P
Campiglia
Isabel
I
Gomez-Monterrey
Luigia
L
Auriemma
Marina
M
Sala
Cristina
C
Marcozzi
Roberta
R
d'Emmanuele di Villa Bianca
Diego
D
Brancaccio
Paolo
P
Rovero
Paolo
P
Santicioli
Stefania
S
Meini
Carlo A
CA
Maggi
Ettore
E
Novellino
D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000737:chemistry / Q000494:pharmacology
D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; C466635:aspartyl-cyclo(penicillamyl-phenylalanyl-tryptophyl-lysyl-tyrosyl-cysteinyl)valine; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-