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

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 (h U-II) peptide in which, along with well-...

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Published in:Journal of medicinal chemistry 2024-08, Vol.67 (16), p.13879-13890
Main Authors: Merlino, Francesco, Secondo, Agnese, Mitidieri, Emma, Sorrentino, Raffaella, Bellavita, Rosa, Grasso, Nicola, Chatenet, David, Pannaccione, Anna, Grieco, Paolo, d’Emmanuele di Villa Bianca, Roberta, Carotenuto, Alfonso
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Animals
CHO Cells
Cricetulus
HEK293 Cells
Humans
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
Structure-Activity Relationship
Urotensins - chemistry
Urotensins - metabolism
Urotensins - pharmacology
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Summary: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 (h U-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 h U-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 h U-II analogues and, furthermore, will aim to elucidate the intricate nature of such a GPCR system.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00688