title: 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.
abstract: 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.
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden.
authors.forename: André
authors.initials: A
authors.lastname: Holdfeldt
authors.affiliation: the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and.
authors.forename: Sarah Line
authors.initials: SL
authors.lastname: Skovbakke
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden.
authors.forename: Malene
authors.initials: M
authors.lastname: Winther
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Gabl
authors.affiliation: the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and.
authors.forename: Christina
authors.initials: C
authors.lastname: Nielsen
authors.affiliation: the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and.
authors.forename: Iris
authors.initials: I
authors.lastname: Perez-Gassol
authors.affiliation: the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and.
authors.forename: Camilla Josephine
authors.initials: CJ
authors.lastname: Larsen
authors.affiliation: the Cancer and Inflammation Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
authors.affiliation: From the Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 405 30, Sweden, Huamei.forsman@rheuma.gu.se.
authors.forename: Huamei
authors.initials: H
authors.lastname: Forsman
authors.affiliation: the Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, and.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007850:Lauric Acids / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: C105101:FPR2 protein, human; D007850:Lauric Acids; D057786:Peptidomimetics; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse; C030358:lauric acid; D019255:NADPH Oxidases
keywords: G-protein-coupled receptor (GPCR); NADPH oxidase; inflammation; neutrophil; receptor structure-function; structure-function