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JOURNAL ARTICLE

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist

Sebastian Bandholtz, Sarah Erdmann, Jan Lennart von Hacht, Samantha Exner, Gerd Krause, Gunnar Kleinau, Carsten Grötzinger
Journal of Medicinal Chemistry 2016 November 23, 59 (22): 10100-10112
27791374
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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