- Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides
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In accordance with their common but also divergent physiological actions, human urotensin II (1) and urotensin II-related peptide (2) could stabilize specific urotensin II receptor (UTR) conformations, thereby activating different signaling pathways, a feature referred to as biased agonism or functional selectivity. Sequential N-methylation of the amides in the conserved core sequence of 1, 2, and fragment U-II4-11 (3) shed light on structural requirements involved in their functional selectivity. Thus, 18 N-methylated UTR ligands were synthesized and their biological profiles evaluated using in vitro competition binding assays, ex vivo rat aortic ring bioassays and BRET-based biosensor experiments. Biological activity diverged from that of the parent structures contingent on the location of amide methylation, indicating relevant hydrogen-bond interactions for the function of the endogenous peptides. Conformational analysis of selected N-methyl analogs indicated the importance of specific amide residues of 2 for the distinct pharmacology relative to 1 and 3.
- Merlino, Francesco,Billard, étienne,Yousif, Ali M.,Di Maro, Salvatore,Brancaccio, Diego,Abate, Luigi,Carotenuto, Alfonso,Bellavita, Rosa,D'Emmanuele Di Villa Bianca, Roberta,Santicioli, Paolo,Marinelli, Luciana,Novellino, Ettore,Hébert, Terence E.,Lubell, William D.,Chatenet, David,Grieco, Paolo
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- Agonists and antagonists of the urotensinergic system
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Novel urotensin II receptor (UT) agonists and antagonists are described herein. More specifically, novel derivatives of urotensin II-related peptide (URP) are described herein.
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Page/Page column 39; 40; 49; 51
(2016/06/06)
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- An investigation into the origin of the biased agonism associated with the urotensin II receptor activation
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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). Exte
- Brancaccio, Diego,Merlino, Francesco,Limatola, Antonio,Yousif, Ali Munaim,Gomez-Monterrey, Isabel,Campiglia, Pietro,Novellino, Ettore,Grieco, Paolo,Carotenuto, Alfonso
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p. 392 - 399
(2015/05/13)
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- Eco-friendly combination of the immobilized PGA enzyme and the s-phacm protecting group for the synthesis of cys-containing peptides
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Enzyme-labile protecting groups have emerged as a green alternative to conventional protecting groups. These groups introduce a further orthogonal dimension and eco-friendliness into protection schemes for the synthesis of complex polyfunctional organic molecules. S-Phacm, a Cys-protecting group, can be easily removed by the action of a covalently immobilized PGA enzyme under very mild conditions. Herein, the versatility and reliability of an eco-friendly combination of the immobilized PGA enzyme and the S-Phacm protecting group has been evaluated for the synthesis of diverse Cys-containing peptides.
- Góngora-Benítez, Miriam,Basso, Alessandra,Bruckdorfer, Thomas,Royo, Miriam,Tulla-Puche, Judit,Albericio, Fernando
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p. 16166 - 16176
(2013/02/23)
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