The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase.

The Journal of biological chemistry 2016 Sep 16

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Neutrophils expressing formyl peptide receptor 2 (FPR2) play key roles in host defense, immune regulation, and resolution of inflammation. Consequently, the search for FPR2-specific modulators has attracted much attention due to its therapeutic potential. Earlier described agonists for this receptor display potent activity for the human receptor (FPR2) but low activity for the mouse receptor orthologue (Fpr2), rendering them inapplicable in murine models of human disease. Here we describe a novel FPR2 agonist, the proteolytically stable α-peptide/β-peptoid hybrid Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 (F2M2), showing comparable potency in activating human and mouse neutrophils by inducing a rise in intracellular Ca(2+) concentration and assembly of the superoxide-generating NADPH oxidase. This FPR2/Fpr2 agonist contains a headgroup consisting of a 2-aminooctanoic acid (Aoc) residue acylated with lauric acid (C12 fatty acid), which is linked to a peptide/peptoid repeat ((Lys-βNphe)6-NH2). Both the fatty acid moiety and the (S)-Aoc residue were required for FPR2/Fpr2 activation. This type of proteolytically stable FPR2-specific peptidomimetics may serve as valuable tools for future analysis of FPR2 signaling as well as for development of prophylactic immunomodulatory therapy. This novel class of cross-species FPR2/Fpr2 agonists should enable translation of results obtained with mouse neutrophils (and disease models) into enhanced understanding of human inflammatory and immune diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Citation

André Holdfeldt, Sarah Line Skovbakke, Malene Winther, Michael Gabl, Christina Nielsen, Iris Perez-Gassol, Camilla Josephine Larsen, Ji Ming Wang, Anna Karlsson, Claes Dahlgren, Huamei Forsman, Henrik Franzyk. The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase. The Journal of biological chemistry. 2016 Sep 16;291(38):19888-99