title: Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.
abstract: This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO2)-Abu), shows low nanomolar potency as well as improved metabolic stability.
authors: Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
authors: Sebastian
authors: S
authors: Bandholtz
authors: Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
authors: Sarah
authors: S
authors: Erdmann
authors: Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
authors: Jan Lennart
authors: JL
authors: von Hacht
authors: Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
authors: Samantha
authors: S
authors: Exner
authors: Leibniz-Institut für Molekulare Pharmakologie , 13125 Berlin, Germany.
authors: Gerd
authors: G
authors: Krause
authors: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin , D-13353 Berlin, Germany.
authors: Gunnar
authors: G
authors: Kleinau
authors: Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
authors: Carsten
authors: C
authors: Grötzinger
mesh_terms: D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; C000620072:urolinin