title: Structure-Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9.
abstract: Previous modifications of the peptide sequence of human urotensin-II (U-II) led to the identification of two well-known ligands: P5U and urantide. These derivatives are considered to be the most representative agonist and antagonist, respectively, at the human urotensin receptor (UT). Optimization of P5U and urantide was carried out to stabilize specific conformations that may suggest new elements for discriminating agonist versus antagonist activity. We studied novel derivatives containing uncoded amino acids. In particular, the Tyr(9) residue of both P5U and urantide was replaced with nonaromatic hydrophobic bulky residues, as well as conformationally constrained aromatic moieties to generate eight novel derivatives. These analogues further contributed to determining the influence of such residues on binding affinity for and biological activity at UT. One of these eight peptides was also investigated by NMR spectroscopy and docking studies owing to its peculiar conformational properties and mode of interaction with UT. This structure-activity study is aimed at a more thorough examination of the role of tyrosine in modulating the agonism/antagonism of human U-II.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merlino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Yousif
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Piras
authors.affiliation: Department of Pharmacy, University of Salerno, 84084, Fisciano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gomez-Monterrey
authors.affiliation: Department of Pharmacology, Menarini Ricerche, via Rismondo 12A, 50131, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Santicioli
authors.affiliation: Department of Pharmacology, Menarini Ricerche, via Rismondo 12A, 50131, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Meini
authors.affiliation: Department of Pharmacology, Menarini Ricerche, via Rismondo 12A, 50131, Florence, Italy.
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Maggi
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy. paolo.grieco@unina.it.|Centro Interuniversitario di Ricerca sui Peptidi Bioattivi (CIRPEB), University of Naples "Federico II" and DFM-Scarl, Institute of Biostructures and Bioimaging-CNR, Via Mezzocannone 16, 80134, Naples, Italy. paolo.grieco@unina.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D010446:Peptide Fragments; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-
keywords: P5U; docking; structure-activity relationships; urantide; urotensin-II