Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist

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.