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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.
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.
Afiliación
  • Merlino F; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Secondo A; Centro Interuniversitario di Ricerca sui Peptidi Bioattivi "Carlo Pedone" (CIRPeB), University of Naples Federico II, via Mezzocannone 16, 80134 Naples, Italy.
  • Mitidieri E; 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.
  • Sorrentino R; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Bellavita R; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Grasso N; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Chatenet D; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Pannaccione A; Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Université du Québec, H7 V 1B7 Québec, Canada.
  • Grieco P; 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.
  • d'Emmanuele di Villa Bianca R; Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
  • Carotenuto A; Centro Interuniversitario di Ricerca sui Peptidi Bioattivi "Carlo Pedone" (CIRPeB), University of Naples Federico II, via Mezzocannone 16, 80134 Naples, Italy.
J Med Chem ; 67(16): 13879-13890, 2024 Aug 22.
Article en En | MEDLINE | ID: mdl-39096311
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Urotensinas / Receptores Acoplados a Proteínas G Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Urotensinas / Receptores Acoplados a Proteínas G Límite: Animals / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos