The peptidomimetic Lau-(Lys-βNSpe)6-NH2 antagonizes formyl peptide receptor 2 expressed in mouse neutrophils

• Published in: Biochemical pharmacology 2016-11, Vol.119, p.56-65
• Main Authors: Skovbakke, Sarah Line, Winther, Malene, Gabl, Michael, Holdfeldt, André, Linden, Sara, Wang, Ji Ming, Dahlgren, Claes, Franzyk, Henrik, Forsman, Huamei
• Format: Article
• Language: English
• Subjects: Anti-inflammatory; Farmakologi och toxikologi; GPCR; NADPH-oxidase; Pharmacology and Toxicology; Reactive oxygen species; Receptor antagonism
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2016.09.004

The peptidomimetic Lau-(Lys-βNSpe)6-NH2 interacts with the murine Fpr2 and inhibits neutrophil production of reactive oxygen species in response to PSMα2, an Fpr2-specific agonist. Single elements in the graphical abstract are adapted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology, Elzbieta Kolaczkowska and Paul Kubes, Neutrophil recruitment and function in health and inflammation, Nature Rev Immunol 2013, 13, p. 159–175, copyright 2013 and Nature Reviews Immunology, Elzbieta Kolaczkowska and Paul Kubes, Neutrophil recruitment and function in health and inflammation, Copyright 2013 and Chao Shi and Eric G. Pamer, Monocyte recruitment during infection and inflammation, Nature Rev Immunol 2011, 11, p. 762–774, Copyright 2011. [Display omitted] The formyl peptide receptor (FPR) gene family has a complex evolutionary history and comprises eight murine members but only three human representatives. To enable translation of results obtained in mouse models of human diseases, more comprehensive knowledge of the pharmacological similarities/differences between the human and murine FPR family members is required. Compared to FPR1 and FPR2 expressed by human neutrophils, very little is known about agonist/antagonist recognition patterns for their murine orthologues, but now we have identified two potent and selective formylated peptide agonists (fMIFL and PSMα2) for Fpr1 and Fpr2, respectively. These peptides were used to determine the inhibition profile of a set of antagonists with known specificities for the two FPRs in relation to the corresponding murine receptors. Some of the most potent and selective antagonists for the human receptors proved to be devoid of effect on their murine orthologues as determined by their inability to inhibit superoxide release from murine neutrophils upon stimulation with receptor-specific agonists. The Boc-FLFLF peptide was found to be a selective antagonist for Fpr1, whereas the lipidated peptidomimetic Lau-(Lys-βNSpe)6-NH2 and the hexapeptide WRW4 were identified as Fpr2-selective antagonists.