Urantide Conformation and Interaction with the Urotensin‐II Receptor

Abstract

Urotensin II (U-II) is a disulfide bridged peptide hormone identified as the ligand of a G protein-coupled receptor. Human U-II (H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) has been described as the most potent vasoconstrictor compound identified to date. We have previously identified the compound termed urantide (H-Asp-c[Pen-Phe-DTrp-Orn-Tyr-Cys]-Val-OH), which is the most potent UT receptor (UTR) antagonist described to date. Urantide may have potential clinical value in the treatment of atherosclerosis. In the present study, we studied the conformational preferences of urantide in DPC micelles and developed a urantide/UTR interaction model. This model can help the design of novel peptides and small molecules as UTR antagonists.

Structure–Activity Study of the Peptides P5U and Urantide by the Development of Analogues Containing Uncoded Amino Acids at Position 9

“…[47,48] Nevertheless, it has been used as an antagonist reference compound by several research groups in studies of the urotensinergic system. [25,29] Therefore, the request for a pure antagonist peptide remains unmet. Finally, the SAR and conformational results reported herein should provide valuable information in the development of further U-II derivatives, with special interest in the development of antagonists of UT.…”

“…Micelle solution was used, as we have reported the NMR structure of hU-II and other UT agonists [18,23,24] and antagonist [25,26] in this medium.…”

“…45 25 ]SDS. NMR spectra were recorded on a Varian INOVA 700 MHz spectrometer equipped with a z-gradient 5 mm triple-resonance probe head.…”

“…[33,60,61] The initial poses for the UT-peptide 4 complex were generated by docking the lowest-energy conformers of peptide 4 obtained by NMR to the UT model using the program HAD-DOCK 2.0. [34,62] For comparison, the best-scored NMR structures of P5U [23] and urantide [25] were also docked into the same UT model. Regarding urantide, the NMR structure obtained in DPC micelles was used due to its higher reliability as antagonist 3D structure relative to that obtained in SDS as confirmed by the study on other urantide-related peptide antagonists.…”

New directions for urotensin II receptor ligands

“…As previously reported, the trans orientation of the Tyr 9 residue in UII appears to be a key determinant in the agonist/antagonist switch . A further SAR study, performed to evaluate the impact of electron‐rich polycyclic aromatics, or electro‐donating/withdrawing para‐substituted phenylalanine at this particular position, led to the discovery of two superagonists [Btz 9 ]P5U (UPG100) (Figure ) and [3,4‐Cl)Phe 9 ]P5U (UPG92) (Figure ) exhibiting a significantly greater potency than P5U (P5U; pEC 50 = 9.40 ± 0.20, [Btz 9 ]P5U; pEC 50 = 10.71 ± 0.04 and [Btz 9 ]P5U; pEC 50 = 10.90 ± 0.14) in an ex vivo rat aortic contraction bioassay .…”