The peptidomimetic Lau-(Lys-βNSpe)6-NH2antagonizes formyl peptide receptor 2 expressed in mouse neutrophils.
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-NH2and the hexapeptide WRW4were identified as Fpr2-selective antagonists.
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Sarah Line
SL
Skovbakke
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Malene
M
Winther
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Michael
M
Gabl
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
André
A
Holdfeldt
Department of Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Sara
S
Linden
Cancer and Inflammation Program, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Ji Ming
JM
Wang
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address: Claes.Dahlgren@microbio.gu.se.
Claes
C
Dahlgren
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Henrik
H
Franzyk
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
Huamei
H
Forsman
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D055666:Lipopeptides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism*; D057786:Peptidomimetics / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
C469988:Fpr1 protein, mouse; C000618346:Lau-(Lys-betaNSpe)6-NH2; D055666:Lipopeptides; D057786:Peptidomimetics; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse
Anti-inflammatory; GPCR; NADPH-oxidase; Reactive oxygen species; Receptor antagonism