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

  • J Med Chem. 2024 Aug 22;67(16):13879-13890. doi: 10.1021/acs.jmedchem.4c00688.
Francesco Merlino  1  2 ,  Agnese Secondo  3 ,  Emma Mitidieri  1 ,  Raffaella Sorrentino  1 ,  Rosa Bellavita  1 ,  Nicola Grasso  1 ,  David Chatenet  4 ,  Anna Pannaccione  3 ,  Paolo Grieco  1  2 ,  Roberta d'Emmanuele di Villa Bianca  1 ,  Alfonso Carotenuto  1  2
Affiliations
  • 1. Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • 2. Centro Interuniversitario di Ricerca sui Peptidi Bioattivi "Carlo Pedone" (CIRPeB), University of Naples Federico II, via Mezzocannone 16, 80134 Naples, Italy.
  • 3. Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine and Surgery, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy.
  • 4. Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Université du Québec, H7 V 1B7 Québec, Canada.
PMID: 39096311 DOI: 10.1021/acs.jmedchem.4c00688
Abstract

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.

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