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ChemMedChem. 2016 Aug 19;11(16):1856-64. doi: 10.1002/cmdc.201500607. Epub 2016 Apr 9.

Structure-Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9.

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Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
Department of Pharmacy, University of Salerno, 84084, Fisciano, Italy.
Department of Pharmacology, Menarini Ricerche, via Rismondo 12A, 50131, Florence, Italy.
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131, Naples, Italy.
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.


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.


P5U; docking; structure-activity relationships; urantide; urotensin-II

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