title: Structure-activity relationships of urotensin II and URP.
abstract: Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.
authors.affiliation: Inserm U413, Laboratory of Cellular and Molecular Neuroendocrinology, Mont-Saint-Aignan, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
authors.forename: Christophe
authors.initials: C
authors.lastname: Dubessy
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Hassan
authors.initials: H
authors.lastname: Oulyadi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ségalas-Milazzo
authors.forename: Laure
authors.initials: L
authors.lastname: Guilhaudis
authors.forename: Daniel
authors.initials: D
authors.lastname: Davoust
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D036361:Peptide Hormones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D014579:Urotensins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004220:Disulfides; D010446:Peptide Fragments; D036361:Peptide Hormones; D014579:Urotensins; C492079:urotensin II (4-11), Pen(5)-Trp(7)-Orn(8)-; D014443:Tyrosine; C029677:urotensin II; D003545:Cysteine; D000409:Alanine