Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P<sub>1-5</sub>). Increasing numbers of studies have indicated the importance of S1P<sub>3</sub> in various pathophysiological processes. Recently, we have identified a pe...

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Main Authors: Angela Corvino, Ida Cerqua, Alessandra Lo Bianco, Giuseppe Caliendo, Ferdinando Fiorino, Francesco Frecentese, Elisa Magli, Elena Morelli, Elisa Perissutti, Vincenzo Santagada, Giuseppe Cirino, Elisabetta Granato, Fiorentina Roviezzo, Elisa Puliti, Caterina Bernacchioni, Antonio Lavecchia, Chiara Donati, Beatrice Severino
Format: Article
Language:English
Published: MDPI AG 2021-08-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/16/8861
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spelling doaj-59308a81eae347be9c5cb2559c9888a62021-08-26T13:53:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-01228861886110.3390/ijms22168861Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle FibrosisAngela Corvino0Ida Cerqua1Alessandra Lo Bianco2Giuseppe Caliendo3Ferdinando Fiorino4Francesco Frecentese5Elisa Magli6Elena Morelli7Elisa Perissutti8Vincenzo Santagada9Giuseppe Cirino10Elisabetta Granato11Fiorentina Roviezzo12Elisa Puliti13Caterina Bernacchioni14Antonio Lavecchia15Chiara Donati16Beatrice Severino17Department of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50134 Firenze, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50134 Firenze, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyDepartment of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50134 Firenze, ItalyDepartment of Pharmacy, School of Medicine, University of Naples «Federico II», Via D. Montesano 49, 80131 Napoli, ItalyS1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P<sub>1-5</sub>). Increasing numbers of studies have indicated the importance of S1P<sub>3</sub> in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P<sub>3</sub> receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P<sub>3</sub> selective pepducin agonist) and KRX-722 (an S1P<sub>1</sub>-selective pepducin agonist). Those selective towards S1P<sub>3</sub> (compounds <b>V</b> and <b>VII</b>) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.https://www.mdpi.com/1422-0067/22/16/8861sphingosine-1-phosphateS1P<sub>3</sub> receptor antagonistskeletal muscle fibrosismolecular dynamics simulations
collection DOAJ
language English
format Article
sources DOAJ
author Angela Corvino
Ida Cerqua
Alessandra Lo Bianco
Giuseppe Caliendo
Ferdinando Fiorino
Francesco Frecentese
Elisa Magli
Elena Morelli
Elisa Perissutti
Vincenzo Santagada
Giuseppe Cirino
Elisabetta Granato
Fiorentina Roviezzo
Elisa Puliti
Caterina Bernacchioni
Antonio Lavecchia
Chiara Donati
Beatrice Severino
spellingShingle Angela Corvino
Ida Cerqua
Alessandra Lo Bianco
Giuseppe Caliendo
Ferdinando Fiorino
Francesco Frecentese
Elisa Magli
Elena Morelli
Elisa Perissutti
Vincenzo Santagada
Giuseppe Cirino
Elisabetta Granato
Fiorentina Roviezzo
Elisa Puliti
Caterina Bernacchioni
Antonio Lavecchia
Chiara Donati
Beatrice Severino
Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
International Journal of Molecular Sciences
sphingosine-1-phosphate
S1P<sub>3</sub> receptor antagonist
skeletal muscle fibrosis
molecular dynamics simulations
author_facet Angela Corvino
Ida Cerqua
Alessandra Lo Bianco
Giuseppe Caliendo
Ferdinando Fiorino
Francesco Frecentese
Elisa Magli
Elena Morelli
Elisa Perissutti
Vincenzo Santagada
Giuseppe Cirino
Elisabetta Granato
Fiorentina Roviezzo
Elisa Puliti
Caterina Bernacchioni
Antonio Lavecchia
Chiara Donati
Beatrice Severino
author_sort Angela Corvino
title Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
title_short Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
title_full Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
title_fullStr Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
title_full_unstemmed Antagonizing S1P<sub>3</sub> Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
title_sort antagonizing s1p<sub>3</sub> receptor with cell-penetrating pepducins in skeletal muscle fibrosis
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1661-6596
1422-0067
publishDate 2021-08-01
description S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P<sub>1-5</sub>). Increasing numbers of studies have indicated the importance of S1P<sub>3</sub> in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P<sub>3</sub> receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P<sub>3</sub> selective pepducin agonist) and KRX-722 (an S1P<sub>1</sub>-selective pepducin agonist). Those selective towards S1P<sub>3</sub> (compounds <b>V</b> and <b>VII</b>) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.
topic sphingosine-1-phosphate
S1P<sub>3</sub> receptor antagonist
skeletal muscle fibrosis
molecular dynamics simulations
url https://www.mdpi.com/1422-0067/22/16/8861
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