The Experts below are selected from a list of 1821 Experts worldwide ranked by ideXlab platform
David Chatenet - One of the best experts on this subject based on the ideXlab platform.
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New directions for Urotensin II receptor ligands
Peptide Science, 2018Co-Authors: Etienne Billard, Hassan Nassour, Mustapha Iddir, Laura Lee-gosselin, Mathilde Poujol De Molliens, David ChatenetAbstract:The Urotensinergic system, formed by a G protein‐coupled receptor (GPCR) termed UT and two endogenous peptide ligands Urotensin II (UII, H‐Glu‐Thr‐Pro‐Asp‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH) and Urotensin II‐related peptide (URP, H‐Ala‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH), is currently regarded as a potential key contributor to cardiovascular functions. While multiple animal studies have shown the therapeutic potential of UT ligands for the treatment of heart failure and atherosclerosis, their lack of efficacy in clinical studies points toward a greater understanding of UT pharmacology at both the molecular and cellular levels. UII and URP are cyclic peptides that share a common and strictly conserved bioactive cyclic core (‐Cys‐Phe‐Trp‐Lys‐Tyr‐Cys‐) but differ by their extracyclic N‐terminal residues. While sharing common biological activity, these two endogenous ligands appear to be functionally selective, displaying different specific effects through the selection/stabilization of particular UT active conformations. Thus, UII and URP should be regarded as two distinct actors in the control of cardiovascular functions. In this regard, more focus on URP biological effects had to be paid, while systematic evaluation of new antagonists against both endogenous ligands appears mandatory. Overall, this review offers an overview of the actual horizon of UT pharmacology, notably concerning the development of biased ligands and allosteric modulators.
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Discovery of New Allosteric Modulators of the Urotensinergic System through Substitution of the Urotensin II-Related Peptide (URP) Phenylalanine Residue
2018Co-Authors: Etienne Billard, Terence E. Hébert, David ChatenetAbstract:Urotensin II (UII) and Urotensin II-related peptide (URP) are functionally selective, suggesting that these two hormones might play distinct physiological role through different interactions with their cognate receptor UT. Hypothesizing that the Phe3 residue of URP, which is also present in UII, is a key-element of its specific UT activation, we evaluated the impact of its replacement by non-natural amino acids in URP. Each compound was evaluated for its ability to bind UT, induce rat aortic ring contraction, and activate Gq, G12, and β-arrestin 1 signaling pathways. Such modifications impaired contractile efficacy, reflected by a reduced aptitude to activate G12 in URP but not in the truncated but equipotent UII4–11. Moreover, we have identified two structurally different UT modulators: [d-Phe(pI)3]URP and [Bip3]URP, which exert a probe-dependent action against UII and URP. These compounds should help us understand the specific roles of these hormones as well as guide further therapeutic development
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
Journal of medicinal chemistry, 2017Co-Authors: Antoine Douchez, Etienne Billard, David Chatenet, Terence E Hebert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the Urotensin II receptor (UT) and differentiates the effects of the endogenous ligands Urotensin II (UII) and Urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Eff...
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insight into the role of Urotensin II related peptide tyrosine residue in ut activation
Biochemical Pharmacology, 2017Co-Authors: Etienne Billard, Myriam Letourneau, Terence E Hebert, David ChatenetAbstract:Abstract While sharing common biological activity, the two endogenous ligands of the G protein-coupled receptor UT, e.g. Urotensin II (UII) and Urotensin II-related peptide (URP), also exhibit distinct effects that could be explained by distinct interactions with their cognate receptor (UT). Accordingly, introduction of a similar substitution at the intracyclic Tyr residue in UII and URP led to compounds with divergent pharmacologic profiles. Hypothesizing that the Tyr 6 residue of URP is a key-element to understand the specific activation of UT by URP, we undertook a study of the structure-activity relationship in which this particular residue was replaced by non-natural and constrained amino acids. Each compound was evaluated for its ability to bind UT, to induce rat aortic ring contraction and to activate Gq and G 12 signaling pathways. We identified [Pep 6 ]URP, that binds UT with an affinity similar to that of URP, but behaves as a biased ligand. Used as an antagonist, this peptide is also able to selectively reduce the maximal aortic contraction of URP but not UII. Our results suggest that the orientation of the Tyr residue can stabilize at least two different conformations of UT, leading to biased signaling and a probe-dependent allosteric effect.
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
2017Co-Authors: Antoine Douchez, Etienne Billard, David Chatenet, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the Urotensin II receptor (UT) and differentiates the effects of the endogenous ligands Urotensin II (UII) and Urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system
Ettore Novellino - One of the best experts on this subject based on the ideXlab platform.
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lipidated peptides derived from intracellular loops 2 and 3 of the Urotensin II receptor act as biased allosteric ligands
Journal of Biological Chemistry, 2021Co-Authors: Hassan Nassour, Myriam Letourneau, Etienne Billard, Tuan Anh Hoang, Ryan D Martin, Juliana C C Dallagnol, Ettore NovellinoAbstract:Over the last decade, the Urotensinergic system, composed of one G protein-coupled receptor and two endogenous ligands, has garnered significant attention as a promising new target for the treatment of various cardiovascular diseases. Indeed, this system is associated with various biomarkers of cardiovascular dysfunctions and is involved in changes in cardiac contractility, fibrosis, and hypertrophy contributing, like the angiotensinergic system, to the pathogenesis and progression of heart failure. Significant investment has been made toward the development of clinically relevant UT ligands for therapeutic intervention, but with little or no success to date. This system therefore remains to be therapeutically exploited. Pepducins and other lipidated peptides have been used as both mechanistic probes and potential therapeutics; therefore, pepducins derived from the human Urotensin II receptor might represent unique tools to generate signaling bias and study hUT signaling networks. Two hUT-derived pepducins, derived from the second and the third intracellular loop of the receptor (hUT-Pep2 and [Trp1, Leu2]hUT-Pep3, respectively), were synthesized and pharmacologically characterized. Our results demonstrated that hUT-Pep2 and [Trp1, Leu2]hUT-Pep3 acted as biased ago-allosteric modulators, triggered ERK1/2 phosphorylation and, to a lesser extent, IP1 production, and stimulated cell proliferation yet were devoid of contractile activity. Interestingly, both hUT-derived pepducins were able to modulate human Urotensin II (hUII)- and Urotensin II-related peptide (URP)-mediated contraction albeit to different extents. These new derivatives represent unique tools to reveal the intricacies of hUT signaling and also a novel avenue for the design of allosteric ligands selectively targeting hUT signaling potentially.
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An investigation into the origin of the biased agonism associated with the Urotensin II receptor activation
Journal of peptide science : an official publication of the European Peptide Society, 2015Co-Authors: Diego Brancaccio, Francesco Merlino, Ali Munaim Yousif, Antonio Limatola, Isabel Gomez-monterrey, Pietro Campiglia, Ettore Novellino, Paolo Grieco, Alfonso CarotenutoAbstract:The Urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. Urotensin II (U-II) and Urotensin II-related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the Urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U-II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U-II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that of hU-II previously determined. Finally, we undertook docking studies between URP, hU-II, and an UT receptor model. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
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Urantide conformation and interaction with the Urotensin-II receptor.
Archiv der Pharmazie, 2013Co-Authors: Diego Brancaccio, Antonio Limatola, Isabel Gomez-monterrey, Pietro Campiglia, Ettore Novellino, Paolo Grieco, Alfonso CarotenutoAbstract: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.
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Urotensin-II receptor antagonists.
Current medicinal chemistry, 2006Co-Authors: A Carotenuto, P Grieco, P Rovero, Ettore NovellinoAbstract:Urotensin-II (U-II) is a "somatostatin-like" cyclic neuropeptide which was originally isolated from goby fish urophysis, and subsequently identified in other species, including man. The interest in human U-II (hU-II) has grown enormously in the last few years, following the identification of a specific human receptor (formerly identified as the GPR14/SENR orphan receptor), now referred to as UT receptor. The U-II/UT system seems to play an important role in cardiovascular functions. hU-II vasoconstrictive potency is reported to be an order of magnitude greater than that of endothelin-1 (ET-1), which would make it the most potent mammalian vasoconstrictor identified to date. hU-II also exerts potent inotropic effects in the human heart in vitro. On the basis of its spectrum of activities, hU-II has been suggested to modulate cardiovascular homeostasis and possibly to be involved in certain cardiovascular pathologies. Central nervous effects of U-II have also been described, in particular, intracerebroventricular administration promotes anxiogenic-like behaviors in rodents. Furthermore, UT receptor overexpression has been observed in some tumor cell lines. Therefore, specific and selective UT receptor antagonists provide useful tools for investigating the (patho)physiological role(s) of the U-II/UT receptor system. In this review we aim to provide an overview of the research in the area of UT receptor antagonists as well as the progress in understanding the role of the U-II/UT system in human (patho)physiology.
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Urotensin-II receptor ligands. From agonist to antagonist activity
Journal of medicinal chemistry, 2005Co-Authors: Paolo Grieco, Alfonso Carotenuto, Pietro Campiglia, P Rovero, Luciana Marinelli, Teresa Lama, Riccardo Patacchini, Paolo Santicioli, Carlo Alberto Maggi, Ettore NovellinoAbstract:Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a 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 termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt 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 study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational method...
Paolo Grieco - One of the best experts on this subject based on the ideXlab platform.
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Urotensin II((4-11)) Azasulfuryl Peptides: Synthesis and Biological Activity.
Journal of Medicinal Chemistry, 2016Co-Authors: Francesco Merlino, Etienne Billard, David Chatenet, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the Urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the Urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and Urotensin II-related peptide (URP) without affecting their potency.
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Urotensin II(4–11) Azasulfuryl Peptides: Synthesis and Biological Activity
2016Co-Authors: Francesco Merlino, David Chatenet, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Étienne Billard, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the Urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4–11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII(4–11) analogs 6–11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6–11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the Urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII(4–11) derivatives 7–9 reduced up to 50% of the effects of UII and Urotensin II-related peptide (URP) without affecting their potency
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An investigation into the origin of the biased agonism associated with the Urotensin II receptor activation
Journal of peptide science : an official publication of the European Peptide Society, 2015Co-Authors: Diego Brancaccio, Francesco Merlino, Ali Munaim Yousif, Antonio Limatola, Isabel Gomez-monterrey, Pietro Campiglia, Ettore Novellino, Paolo Grieco, Alfonso CarotenutoAbstract:The Urotensin II receptor (UTR) has long been studied mainly for its involvement in the cardiovascular homeostasis both in health and disease state. Two endogenous ligands activate UTR, i.e. Urotensin II (U-II) and Urotensin II-related peptide (URP). Extensive expression of the two ligands uncovers the diversified pathophysiological effects mediated by the Urotensinergic system such as cardiovascular disorders, smooth muscle cell proliferation, renal disease, diabetes, and tumour growth. As newly reported, U-II and URP have distinct effects on transcriptional activity, cell proliferation, and myocardial contractile activities supporting the idea that U-II and URP interact with UTR in a distinct manner (biased agonism). To shed light on the origin of the divergent activities of the two endogenous ligands, we performed a conformational study on URP by solution NMR in sodium dodecyl sulfate micelle solution and compared the obtained NMR structure of URP with that of hU-II previously determined. Finally, we undertook docking studies between URP, hU-II, and an UT receptor model. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.
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Urantide conformation and interaction with the Urotensin-II receptor.
Archiv der Pharmazie, 2013Co-Authors: Diego Brancaccio, Antonio Limatola, Isabel Gomez-monterrey, Pietro Campiglia, Ettore Novellino, Paolo Grieco, Alfonso CarotenutoAbstract: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.
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Urotensin-II receptor ligands. From agonist to antagonist activity
Journal of medicinal chemistry, 2005Co-Authors: Paolo Grieco, Alfonso Carotenuto, Pietro Campiglia, P Rovero, Luciana Marinelli, Teresa Lama, Riccardo Patacchini, Paolo Santicioli, Carlo Alberto Maggi, Ettore NovellinoAbstract:Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a 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 termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt 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 study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational method...
William D. Lubell - One of the best experts on this subject based on the ideXlab platform.
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
Journal of medicinal chemistry, 2017Co-Authors: Antoine Douchez, Etienne Billard, David Chatenet, Terence E Hebert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the Urotensin II receptor (UT) and differentiates the effects of the endogenous ligands Urotensin II (UII) and Urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Eff...
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
2017Co-Authors: Antoine Douchez, Etienne Billard, David Chatenet, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the Urotensin II receptor (UT) and differentiates the effects of the endogenous ligands Urotensin II (UII) and Urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system
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Urotensin II((4-11)) Azasulfuryl Peptides: Synthesis and Biological Activity.
Journal of Medicinal Chemistry, 2016Co-Authors: Francesco Merlino, Etienne Billard, David Chatenet, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the Urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the Urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and Urotensin II-related peptide (URP) without affecting their potency.
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Urotensin II(4–11) Azasulfuryl Peptides: Synthesis and Biological Activity
2016Co-Authors: Francesco Merlino, David Chatenet, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Étienne Billard, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the Urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4–11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII(4–11) analogs 6–11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6–11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the Urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII(4–11) derivatives 7–9 reduced up to 50% of the effects of UII and Urotensin II-related peptide (URP) without affecting their potency
P Rovero - One of the best experts on this subject based on the ideXlab platform.
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Urotensin-II receptor antagonists.
Current medicinal chemistry, 2006Co-Authors: A Carotenuto, P Grieco, P Rovero, Ettore NovellinoAbstract:Urotensin-II (U-II) is a "somatostatin-like" cyclic neuropeptide which was originally isolated from goby fish urophysis, and subsequently identified in other species, including man. The interest in human U-II (hU-II) has grown enormously in the last few years, following the identification of a specific human receptor (formerly identified as the GPR14/SENR orphan receptor), now referred to as UT receptor. The U-II/UT system seems to play an important role in cardiovascular functions. hU-II vasoconstrictive potency is reported to be an order of magnitude greater than that of endothelin-1 (ET-1), which would make it the most potent mammalian vasoconstrictor identified to date. hU-II also exerts potent inotropic effects in the human heart in vitro. On the basis of its spectrum of activities, hU-II has been suggested to modulate cardiovascular homeostasis and possibly to be involved in certain cardiovascular pathologies. Central nervous effects of U-II have also been described, in particular, intracerebroventricular administration promotes anxiogenic-like behaviors in rodents. Furthermore, UT receptor overexpression has been observed in some tumor cell lines. Therefore, specific and selective UT receptor antagonists provide useful tools for investigating the (patho)physiological role(s) of the U-II/UT receptor system. In this review we aim to provide an overview of the research in the area of UT receptor antagonists as well as the progress in understanding the role of the U-II/UT system in human (patho)physiology.
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Urotensin-II receptor ligands. From agonist to antagonist activity
Journal of medicinal chemistry, 2005Co-Authors: Paolo Grieco, Alfonso Carotenuto, Pietro Campiglia, P Rovero, Luciana Marinelli, Teresa Lama, Riccardo Patacchini, Paolo Santicioli, Carlo Alberto Maggi, Ettore NovellinoAbstract:Urotensin II (U-II) is a disulfide bridged peptide hormone recently identified as the ligand of a 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 termed urantide, which is the most potent UT receptor peptide antagonist described to date. Our previous conformational studies showed that hU-II and its analogues with agonist activity adopt 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 study on new analogues with agonist/antagonist activity on UT receptor. We investigated their biological activity and performed a conformational analysis by spectroscopic and computational method...
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Urotensin II receptor peptide agonists
Medicinal Research Reviews, 2004Co-Authors: Alfonso Carotenuto, Ettore Novellino, Paolo Grieco, P RoveroAbstract:Urotensin II (U-II) has been known for over 30 years as an important teleost fish hormone, but only recently has it been recognized as the endogenous ligand of a new human G-protein-coupled receptor (GPCR) homologous to the GPR14 orphan receptor from rat. Human U-II was found to be a potent vasoconstrictor, widely distributed in human tissues, possibly contributing to several human cardiovascular diseases. It thus has become a major target of medicinal chemistry research. The common structural feature of U-II peptides from different species is the C-terminal portion, characterized by the disulfide bridged cyclic hexapeptide Cys-Phe-Trp-Lys-Tyr-Cys. The few structure-activity relationship studies reported to date attributed a critical role to this portion, with the Trp-Lys-Tyr motif appearing as the key determinant of U-II bioactivity. Consequently, this shorter cyclic peptide was used as a template for the development of several synthetic analogues, among which a superagonist, termed P5U: H-Asp-cyclo(Pen-Phe-Trp-Lys-Tyr-Cys)-Val-OH. Conformational studies confirmed the important role of hU-II C-terminal cyclic portion, enabling the development of 3D pharmacophore models. These findings should lead to the design of new, potent and selective analogues, acting as agonist or antagonist at the human U-II receptor, finally contributing to a deeper comprehension of the (patho)physiological significance of this peptide.
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unraveling the active conformation of Urotensin II
Journal of Medicinal Chemistry, 2004Co-Authors: Alfonso Carotenuto, Pietro Campiglia, Ettore Novellino, Paolo Grieco, P RoveroAbstract:Urotensin II (U-II) is a disulfide-bridged undecapeptide recently identified as the ligand of an orphan 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.With the aim of elucidating the active conformation of hU-II, we have performed a spectroscopic analysis of hU-II minimal active fragment hU-II(4−11) in different environmental conditions. The analysis indicated that hU-II(4−11) was highly structured in the anisotropic membrane mimetic SDS solution, showing a type II‘ β-turn structure, which is almost unprecedented for l-amino acid peptides. Micelle bound structure of hU-II(4−11) was then compared with those of four synthetic analogues recently synthesized in our lab, bearing modified Cys residues at position 5 and/or position 10 and characterized by different levels of agonist activity. The structures of the active compounds were found to be very similar to that of hU-II(4−11)...
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urantide an ultrapotent Urotensin II antagonist peptide in the rat aorta
British Journal of Pharmacology, 2003Co-Authors: Riccardo Patacchini, Ettore Novellino, Paolo Grieco, P Rovero, Paolo Santicioli, Sandro Giuliani, Carlo Alberto MaggiAbstract:In this study we describe the ability of two human Urotensin-II (hU-II) derivatives [Pen5,Orn8]hU-II(4–11) and [Pen5,DTrp7,Orn8]hU-II(4–11) (urantide) to block hU-II-induced contractions in the rat isolated thoracic aorta. Both compounds competitively antagonized hU-II- induced effects with pKB=7.4±0.06 (n=12) and pKB=8.3±0.09 (n=12), respectively. In contrast, neither [Pen5,Orn8]hU-II(4–11) nor urantide (1 μM each) was able to modify noradrenaline- or endothelin 1-induced contractile effects. At micromolar concentrations, [Pen5,Orn8]hU-II(4–11) produced weak (25% of hU-II maximum) agonist responses in the rat aorta, whereas urantide was totally uneffective as agonist up to 1 μM. In addition, [Pen5,Orn8]hU-II(4–11) and urantide displaced [125I]Urotensin II from specific binding at hU-II recombinant receptors (UT receptors) transfected into CHO/K1 cells (pKi=7.7±0.05, n=4 and pKi=8.3±0.04, n=4, respectively). To our knowledge, urantide is the most potent UT receptor antagonist so far described, and might represent a useful tool for exploring the (patho)physiological role of hU-II in the mammalian cardiovascular system. British Journal of Pharmacology (2003) 140, 1155–1158. doi:10.1038/sj.bjp.0705555