Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis
| Autor: | Fiorentina Roviezzo, Antonio Lavecchia, Elena Morelli, Caterina Bernacchioni, Vincenzo Santagada, Ferdinando Fiorino, Elisa Perissutti, Alessandra Lo Bianco, Chiara Donati, Elisa Puliti, Beatrice Severino, Giuseppe Caliendo, Giuseppe Cirino, Angela Corvino, Ida Cerqua, Francesco Frecentese, Elisabetta Granato, Elisa Magli |
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| Přispěvatelé: | Corvino, A., Cerqua, I., Lo Bianco, A., Caliendo, G., Fiorino, F., Frecentese, F., Magli, E., Morelli, E., Perissutti, E., Santagada, V., Cirino, G., Granato, E., Roviezzo, F., Puliti, E., Bernacchioni, C., Lavecchia, A., Donati, C., Severino, B. |
| Rok vydání: | 2021 |
| Předmět: |
sphingosine-1-phosphate
S1P3 receptor antagonist skeletal muscle fibrosis molecular dynamics simulations Agonist QH301-705.5 medicine.drug_class Catalysis Inorganic Chemistry Skeletal muscle fibrosis chemistry.chemical_compound Molecular dynamics simulation medicine Skeletal muscle fibrosi Sphingosine-1-phosphate Biology (General) Physical and Theoretical Chemistry Pepducin Receptor QD1-999 Molecular Biology Spectroscopy G protein-coupled receptor chemistry.chemical_classification Organic Chemistry General Medicine Receptor antagonist Computer Science Applications Amino acid Chemistry chemistry Biophysics lipids (amino acids peptides and proteins) |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 16 International Journal of Molecular Sciences, Vol 22, Iss 8861, p 8861 (2021) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22168861 |
| Popis: | S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 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 S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) 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. |
| Databáze: | OpenAIRE |
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