| Abstract
| - Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand ofa G-protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-cyclo[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date.We have recently identified both a superagonist of hU-II termed P5U and the compound termedurantide, which is the most potent UT receptor peptide antagonist described to date. Ourprevious conformational studies showed that hU-II and its analogues with agonist activityadopt a well-defined type II‘ β-hairpin structure in anisotropic SDS membrane-like environment.This structural arrangement allows tight contact among the Trp7, Lys8, and Tyr9 side chains,which is fundamental to obtain full agonist activity. Here, we report an extensive SAR studyon new analogues with agonist/antagonist activity on UT receptor. We investigated theirbiological activity and performed a conformational analysis by spectroscopic and computationalmethods. Our goal is to obtain a structure-based model able to explain the agonist/antagonistfunctional switching of these ligands.
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