Design, Synthesis and Biological Activities of New Urotensin II- Related Peptides (URP)

摘要

Several studies have demonstrated that the urotensinergic system, composed of two cyclic peptides namely urotensin II and urotensin II-related peptide, was involved in numerous biological processes in normal and pathological states [1,2]. Both peptides mediate their actions through the activation of a specific G-protein coupled receptor (UT), belonging to the 1A subclass of the GPCR family, originally designated as sensory epithelial neuropeptide-like receptor (SENR) or GPR14 [3]. Up to now, the urotensin II peptides are being considered as the most potent vasoconstrictors identified so far. Based on their blood pressure-independent trophic and mitogenic actions, it has been suggested that UII and URP exert specific functions in pathological processes such as myocardial hypertrophy and fibrosis, vascular smooth muscle cell proliferation, atherosclerosis, and diabetic nephropathy [4]. Spectroscopic analysis of hU-II minimal active fragment, hUII(4-11), in which only the amino acid adjacent to the cyclic core differs from URP (Asp in hUII(4-ll) versus Ala in URP), revealed a highly structured compound in SDS with a type II' β-turn structure [5]. Conversely, the conformation of URP, investigated in aqueous solution, demonstrated the presence of an inverse y-turn centered on the Trp~4-Lys~5-Tyr~6 sequence, and an intramolecular hydrogen bond (i, i+2) between the C=0 of Tip~4 and the NH of Tyr~6 [3].