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Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides

Merlino, Francesco; Billard, Étienne; Yousif, Ali Munaim; Di Maro, Salvatore; Brancaccio, Diego; Abate, Luigi; Carotenuto, Alfonso; Bellavita, Rosa; d'Emmanuele di Villa Bianca, Roberta; Santicioli, Paola; Marinelli, Luciana; Novellino, Ettore; Hébert, Terence E; Lubell, William D; Chatenet, David; Grieco, Paolo (2019). Functional Selectivity Revealed by N-Methylation Scanning of Human Urotensin II and Related Peptides Journal of Medicinal Chemistry , vol. 62 , nº 3. p. 1455-1467. DOI: 10.1021/acs.jmedchem.8b01601.

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Résumé

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.

Type de document: Article
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 08 août 2019 01:33
Dernière modification: 08 août 2019 01:33
URI: http://espace.inrs.ca/id/eprint/8148

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