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Conflitti_2023_acsomega
Journal article

Discovery of a novel class of dual GPBAR1 agonists–RORγt inverse agonists for the treatment of IL-17-mediated disorders

  • Fiorillo, Bianca Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Roselli, Rosalinda Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Finamore, Claudia Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Biagioli, Michele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  • Di Giorgio, Cristina Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  • Bordoni, Martina Precision BioTherapeutics, Perugia, Italy
  • Conflitti, Paolo Euler Institute (EUL), Università della Svizzera italiana, Switzerland
  • Marchianò, Silvia Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  • Bellini, Rachele Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  • Rapacciuolo, Pasquale Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Cassiano, Chiara Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Limongelli, Vittorio ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
  • Sepe, Valentina ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Catalanotti, Bruno ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy
  • Fiorucci, Stefano Department of Medicine and Surgery, University of Perugia, Perugia, Italy
  • Zampella, Angela ORCID Department of Pharmacy, University of Naples "Federico II", Naples, Italy
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  • 2023
Published in:
  • ACS Omega. - 2023, vol. 8, no. 6, p. 5983–5994
Agonists
Anatomy
Ligands
Receptors
Rodent models
English Retinoic acid receptor-related orphan receptor γ-t (RORγt) and GPBAR1, a transmembrane G-protein-coupled receptor for bile acids, are attractive drug targets to develop clinically relevant small modulators as potent therapeutics for autoimmune diseases. Herein, we designed, synthesized, and evaluated several new bile acid-derived ligands with potent dual activity. Furthermore, we performed molecular docking and MD calculations of the best dual modulators in the two targets to identify the binding modes as well as to better understand the molecular basis of the inverse agonism of RORγt by bile acid derivatives. Among these compounds, 7 was identified as a GPBAR1 agonist (EC50 5.9 μM) and RORγt inverse agonist (IC50 0.107 μM), with excellent pharmacokinetic properties. Finally, the most promising ligand displayed robust anti-inflammatory activity in vitro and in vivo in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.
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Language
  • English
Classification
Medicine
License
CC BY-NC-ND
Open access status
green
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Persistent URL
https://n2t.net/ark:/12658/srd1328338
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