The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2

Skovbakke, Sarah Line; Heegaard, Peter M. H.; Larsen, Camilla Josephine; Franzyk, Henrik; Forsman, Huamei; Dahlgren, Cláes

doi:10.1016/j.bcp.2014.11.004

Cited by 20 publications

(41 citation statements)

References 72 publications

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“…It has been proposed that when it comes to the action of a pepducin, the fatty acid anchors the molecule in the cell membrane, facilitating interaction between the peptide part and the receptor at the signaling interface (40). However, comparison of the structure-activity relationships for analogues of the FPR2-activating peptidomimetic F2M2 with those of the FPR2-inhibiting F2M1 described earlier (22) reveals differences in the optimal length of the N-terminal fatty acid for activation (12 carbons) and inhibition (at least 16 carbons). If the N-terminal fatty acid in these FPR2 ligands merely anchors the compounds in the lipid bilayer, it would be expected that the optimal length would be similar for agonists and antagonists; however, the observation that longer fatty acids (palmitoyl and myristoyl) are less favorable than the less membrane-interacting Lau moiety rather suggests an affinityrelated role for the N-terminal fatty acid.…”

Section: Variation Of Hydrophobic Amino Acidmentioning

confidence: 99%

“…The two FPR2-specific inhibitors PBP 10 and F2M1 (22,23) both completely abolished the response induced by F2M2 (Fig. 4B).…”

Section: The Peptidomimetic F2m2 (Lau-((s)-aoc)-(lys-␤nphementioning

confidence: 99%

“…Structure-activity relationships for F2M1 (FPR2 antagonist) and F2M2 (FPR2 agonist) demonstrate an essential role of the fatty acid in mediating the interaction of these peptidomimetics with FPR2/Fpr2 (this study and Ref. 22). Although the fatty acid plays a key role in FPR2 modulation, it is not simply a molecular pattern recognized by FPR2 because many ligands lacking a fatty acid moiety bind to FPR2, and many lipidated peptides/peptidomimetics are devoid of activity.…”

Section: Variation Of Hydrophobic Amino Acidmentioning

confidence: 99%

“…6 -NH 2 ) Activates the NADPH Oxidase in Human Neutrophils-In an earlier study, an array of peptidomimetics representing different structural subclasses was screened, using the neutrophil NADPH oxidase assay as a read-out system (25,26). A potent FPR2-specific antagonist was identified (22), and in addition, compounds displaying other lipid headgroups were found to partially inhibit the activity induced by known FPR2-specific agonists. This finding was not further explored, but we now show that the peptidomimetic F2M2 (i.e.…”

mentioning

confidence: 99%

“…We have previously identified a novel class of FPR2 antagonists by screening an array of peptidomimetics comprising several subclasses of ␣-peptide/␤-peptoid hybrids (see Fig. 1B for generic structures), using GPCR-dependent neutrophil production of superoxide as a read-out (22). Among these compounds, the most promising FPR2-interacting peptidomimetic, palmitoyl-(Lys-␤NSpe) 6 -NH 2 (F2M1 in Fig.…”

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confidence: 99%

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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

Holdfeldt

Skovbakke

Winther

et al. 2016

Journal of Biological Chemistry

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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 ␣-peptide/␤-pep- The molecular basis for directional neutrophil migration toward inflammatory sites is their ability to sense "danger signals" produced by microorganisms (i.e. pathogen-associated molecular patterns) and damaged host cells or tissues (i.e. damage-associated molecular patterns) (1). Human neutrophils express two members of the formyl peptide receptor family (FPR1 3 and FPR2), belonging to the family of G-protein-coupled receptors (GPCRs), which recognize pathogen-associated molecular patterns in the form of peptides with an N-terminal formyl-methionine residue, originating from bacterial (and mitochondrial) protein synthesis (2, 3). In addition, human neutrophils express GPCRs that recognize endogenous chemoattractants and damage-associated molecular patterns, including the split product of complement component C5 (C5a, recognized by C5aR), leukotriene LTB 4 (recognized by BLT1), the chemokine IL-8 (CXCL8, recognized by CXCR1 and CXCR2), platelet-activating factor (PAF, recognized by PAFR), and the nucleotide ATP (recognized by P2Y 2 R) (4, 5). Although the two human neutrophil FPRs, FPR1 and FPR2, display significant sequence similarity, they have distinct, albeit partially overlapping, ligand recognition profiles (2, 6, 7).The mouse genome contains at least eight mouse Fprs, among which Fpr1 and Fpr2 are regarded as the orthologues of the receptors expressed in human neutrophils (8, 9). Studies using mice deficient in Fpr1 or Fpr2 have demonstrated roles of these receptors not only in host defense but also in immune regulation and in the resolution of inflammation (10 -12). The therapeutic potential of targeting these receptors in inflammatory/infectious conditions, such as atherosclerosis, cancer, neurodegenerative diseases, and sepsis (see a recent review (13)), justifies the search for receptor-specific ligands that can function as agonists, antagonists, or allosteric modulators. However, a direct translation of knowledge between humans and

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Section: Variation Of Hydrophobic Amino Acidmentioning

confidence: 99%

“…The two FPR2-specific inhibitors PBP 10 and F2M1 (22,23) both completely abolished the response induced by F2M2 (Fig. 4B).…”

Section: The Peptidomimetic F2m2 (Lau-((s)-aoc)-(lys-␤nphementioning

confidence: 99%

Section: Variation Of Hydrophobic Amino Acidmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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

Holdfeldt

Skovbakke

Winther

et al. 2016

Journal of Biological Chemistry

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Studies on acid stability and solid-phase block synthesis of peptide–peptoid hybrids: ligands for formyl peptide receptors

et al. 2018

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Antiviral activity of formyl peptide receptor 2 antagonists against influenza viruses

et al. 2017

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Influenza viruses are one of the most important respiratory pathogens worldwide, causing both epidemic and pandemic infections. The aim of the study was to evaluate the effect of FPR2 antagonists PBP10 and BOC2 on influenza virus replication. We determined that these molecules exhibit antiviral effects against influenza A (H1N1, H3N2, H6N2) and B viruses.FPR2 antagonists used in combination with oseltamivir showed additive antiviral effects.Mechanistically, the antiviral effect of PBP10 and BOC2 is mediated through early inhibition of virus-induced ERK activation. Finally, our preclinical studies showed that FPR2 antagonists protected mice from lethal infections induced by influenza, both in a prophylactic and therapeutic manner. Thus, FPR2 antagonists might be explored for novel treatments against influenza.

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The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2

Cited by 20 publications

References 72 publications

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 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

Studies on acid stability and solid-phase block synthesis of peptide–peptoid hybrids: ligands for formyl peptide receptors

Antiviral activity of formyl peptide receptor 2 antagonists against influenza viruses

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