Urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type 1-triggered cell migration

摘要

Abstract The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration. We and others have previously documented that the uPAR(84–95) sequence, interacts with the formyl peptide receptors (FPR)s, henceforth inducing cell migration of several cell lines, including leukocytes, and the synthetic shorter peptide (Ser 88 -Arg-Ser-Arg-Tyr 92 , SRSRY) retains chemotactic activity in?vitro and in?vivo . Recently, we have developed the head-to-tail cyclic analog [SRSRY], a new potent and stable inhibitor of monocyte trafficking. This prompted us to develop novel cyclic and linear analogs of [SRSRY] with the aim to broaden the knowledge about structure-activity relationships of peptide [SRSRY]. Herein we report their synthesis, effects on cell migration, conformational and docking analyses which served to envisage a new pharmacophore model for inhibitors of FPR1-triggered cell migration. Graphical abstract Display Omitted Highlights ? Novel peptide analogs of urokinase receptor-derived SRSRY peptide. ? SAR study supported by the effect of the new generated pentapeptides on FPR1 internalization. ? Inhibitors of Formyl Peptide Receptor type 1-mediated cell Migration. ? Conformational studies: CD and NMR spectroscopy analyses. ? Docking and MD simulations studies.