Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

Abstract

Urotensin-II was originally isolated from the goby urophysis in the 1960s as a vasoactive peptide with a prominent role in cardiovascular homeostasis. The identification of human isoform of urotensin-II and its specific UT receptor by Ames et al. in 1999 led to investigating the putative role of the interaction U-II/UT receptor in multiple pathophysiological effects in humans. Since urotensin-II is widely expressed in several peripheral tissues including cardiovascular system, the design and development of novel urotensin-II analogues can improve knowledge about structure-activity relationships (SAR). In particular, since the modulation of the U-II system offers a great potential for therapeutic strategies related to the treatment of several diseases, like cardiovascular diseases, the research of selective and potent ligands at UT receptor is more fascinating. In this paper, we review the developments of peptide and nonpeptide U-II structures so far developed in order to contribute also to a more rational and detectable design and synthesis of new molecules with high affinity at the UT receptor.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…Structure-activity relationship studies (Flohr et al, 2002;Kinney et al, 2002;Brkovic et al, 2003;Labarrère et al, 2003;Chatenet et al, 2004;Guerrini et al, 2005;Leprince et al, 2008;Merlino et al, 2013) led to the discovery of peptide-derived analogs acting as potent agonists or antagonists (Behm et al, 2002;Grieco et al, 2002a;Herold et al, 2003;Patacchini et al, 2003;Carotenuto et al, 2004b;Grieco et al, 2005;Carotenuto et al, 2006;Chatenet et al, 2012Chatenet et al, , 2013a. However, those molecules are usually not considered as the best drug candidates, because their pharmacodynamic and pharmacokinetic properties (bioavailability, metabolic stability, biodistribution) are not optimal.…”

“…This section represents a summary of nonpeptidic ligands for the urotensinergic system; more information can be obtained in the reviews from Cosenzi (2008), Lescot et al (2008a), Maryanoff and Kinney (2010), and Merlino et al (2013). Thus, the literature shows that most major pharmaceutical companies are involved in a research program aimed at designing highly potent agonists and antagonists of the UT receptor.…”

“…Clinical studies have provided evidence that UII and UT are implicated in various pathologies, including cardiovascular diseases Ng et al, 2002;Richards et al, 2002;You et al, 2012;Watson et al, 2013), renal diseases , and diabetes (Wenyi et al, 2003;Sidharta et al, 2009). The various activities of UII and the potential implication of the urotensinergic system in various pathologies have prompted academic laboratories and pharmaceutical companies to design specific agonists and antagonists that are currently used for basic research and may lead to therapeutic applications Maryanoff and Kinney, 2010;Tsoukas et al, 2011;Merlino et al, 2013).…”

Conformation and Dynamics of Human Urotensin II and Urotensin Related Peptide in Aqueous Solution

“…URP has been suggested from the NMR experiments by Chatenet et al 15 to have an inverse 4,5,6 γ-turn 31 however, suggest structural flexibility in aqueous solution and a high similarity of URP and UII ring conformations. Carotenuto et al 28 made NMR studies of UII and the smaller URP-like version, UII (4)(5)(6)(7)(8)(9)(10)(11), in sodium dodecyl sulfate (SDS) micelles mimicking a cell-surface environment. They found two slowly exchanging states: one specified as β-hairpin with a β-turn type II' centered at W 7 and K 8 and another weakly populated, apparently, with a more flexible and random structure.…”

“…7 The length of the N-terminus of human UII is four residues but this is species variable, so that the total peptide length ranges from 11 residues for human UII up to 17 for hamster UII. [7][8][9][10] Urotensin related peptide (URP) is a paralog of UII. 11 It has the same Cterminal cyclic moiety as UII but the extra-annular N-terminus of UII is replaced by a single alanine at position 1 in URP (Scheme 1).…”