Merlino, Francesco; Secondo, Agnese; Mitidieri, Emma; Sorrentino, Raffaella; Bellavita, Rosa; Grasso, Nicola; Chatenet, David 
ORCID: https://orcid.org/0000-0002-7270-4328; Pannaccione, Anna; Grieco, Paolo; d’Emmanuele di Villa Bianca, Roberta et Carotenuto, Alfonso
(2024).
Expanding Structure-Activity Relationships of Human Urotensin II Peptide Analogues: A Proposed Key Role of the N-Terminal Region for Novel Urotensin II Receptor Modulators
Journal of Medicinal Chemistry
, vol. ahead
.
pp. 1-12.
DOI: 10.1021/acs.jmedchem.4c0068.
(Sous Presse)
Résumé
While the urotensinergic system plays a role in influencing various pathologies, its potential remains untapped because of the absence of therapeutically effective urotensin II receptor (UTR) modulators. Herein, we developed analogues of human urotensin II (hU-II) peptide in which, along with well-known antagonist-oriented modifications, the Glu1 residue was subjected to single-point mutations. The generated library was tested by a calcium mobilization assay and ex vivo experiments, also in competition with selected ligands. Interestingly, many derivatives showed noncompetitive modulation that was rationalized by the lateral allostery concept applied to a G protein-coupled receptor (GPCR) multimeric model. UPG-108 showed an unprecedented ability to double the efficacy of hU-II, while UPG-109 and UPG-111 turned out to be negative allosteric modulators of UTR. Overall, our investigation will serve to explore and highlight the expanding possibilities of modulating the UTR system through N-terminally modified hU-II analogues and, furthermore, will aim to elucidate the intricate nature of such a GPCR system.
| Type de document: | Article |
|---|---|
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 11 août 2024 07:43 |
| Dernière modification: | 11 août 2024 07:43 |
| URI: | https://espace.inrs.ca/id/eprint/15929 |
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