Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis.

International journal of molecular sciences 2021 Aug 17

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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.

Citation

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 S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis. International journal of molecular sciences. 2021 Aug 17;22(16)