Antagonizing S1P Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Aug 27

PMID 34445567

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

Affiliations

Soon will be listed here.

Abstract

S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P). Increasing numbers of studies have indicated the importance of S1P in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P 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 selective pepducin agonist) and KRX-722 (an S1P-selective pepducin agonist). Those selective towards S1P (compounds and ) 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.

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