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J Med Chem. 2016 Nov 23;59(22):10100-10112. Epub 2016 Nov 4.

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist.

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Campus Virchow-Klinikum, Department of Hepatology and Gastroenterology and Molecular Cancer Research Center (MKFZ), Charité-Universitätsmedizin Berlin , Augustenburger Platz 1, D-13353 Berlin, Germany.
Leibniz-Institut für Molekulare Pharmakologie , 13125 Berlin, Germany.
Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin , D-13353 Berlin, Germany.


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.

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