Receptors for chemotactic formyl peptides as pharmacological targets

Le, Yingying; Yang, Yiming; Cui, You‐Hong; Yazawa, Hiroyuki; Gong, Wanghua; Qiu, Cunping; Wang, Ji Ming

doi:10.1016/s1567-5769(01)00150-3

Cited by 84 publications

(84 citation statements)

References 106 publications

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“…N-formyl peptides, such as fMLP, are some of the first identified and most potent chemoattractants for phagocytic leukocytes (16). In all organisms, protein synthesis is initiated with a methionine residue which can be removed during protein maturation.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibiting this response would benefit any invading organism, and therefore, CHIPS could be an important virulence strategy (29) of S. aureus and a new potential target in the treatment of S. aureus infections. Also, chemokine receptors are obvious targets for drug development because they have presumed roles in disease processes (16). During the past few years, progress has been made in the understanding of the biological roles of once elusive FPR.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with these molecules, the affinity and potency of CHIPS to bind and block the FPR is at least 1000-fold higher (32). The unique properties of CHIPS to specifically inhibit the FPR with high affinity could be an important new tool to further stimulate the fundamental research on the mechanisms underlying the FPR and its role in disease processes (16,17,32,33).…”

Section: Discussionmentioning

confidence: 99%

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N-Terminal Residues of the Chemotaxis Inhibitory Protein of Staphylococcus aureus Are Essential for Blocking Formylated Peptide Receptor but Not C5a Receptor

Haas

Kleibeuker

et al. 2004

The Journal of Immunology

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Staphylococcus aureus excretes a factor that specifically and simultaneously acts on the C5aR and the formylated peptide receptor (FPR). This chemotaxis inhibitory protein of S. aureus (CHIPS) blocks C5a- and fMLP-induced phagocyte activation and chemotaxis. Monoclonal anti-CHIPS Abs inhibit CHIPS activity against one receptor completely without affecting the other receptor, indicating that two distinct sites are responsible for both actions. A CHIPS-derived N-terminal 6 aa peptide is capable of mimicking the anti-FPR properties of CHIPS but has no effect on the C5aR. Synthetic peptides in which the first 6 aa are substituted individually for all other naturally occurring amino acids show that the first and third residue play an important role in blocking the FPR. Using an Escherichia coli expression system, we created mutant CHIPS proteins in which these amino acids are substituted. These mutant proteins have impaired or absent FPR- but still an intact C5aR-blocking activity, indicating that the loss of the FPR-blocking activity is not caused by any structural impairment. This identifies the first and third amino acid, both a phenylalanine, to be essential for CHIPS blocking the fMLP-induced activation of phagocytes. The unique properties of CHIPS to specifically inhibit the FPR with high affinity (kd = 35.4 ± 7.7 nM) could be an important new tool to further stimulate the fundamental research on the mechanisms underlying the FPR and its role in disease processes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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N-Terminal Residues of the Chemotaxis Inhibitory Protein of Staphylococcus aureus Are Essential for Blocking Formylated Peptide Receptor but Not C5a Receptor

Haas

Kleibeuker

et al. 2004

The Journal of Immunology

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“…Members of the FPR family also play an important role in host defense against pathogens (8,9) and have been identified in association with three cell surface G proteins as follows: FPR1 (FPR), FPR2 (FPRL1), and FPR3 (FPRL2) (8,9). Additionally, several ligands in the FPR family have been identified, including a bacterial peptide N-formyl-MetLeu-Phe (fMLF), HIV-1 envelope peptides (T20 and T21), hostderived agonist annexin I, and a synthetic peptide (Trp-Lys-TyrMet-Val-D-Met (WKYMVm)) (10 -13).…”

mentioning

confidence: 99%

Functional Expression of Formyl Peptide Receptor Family in Human NK Cells

Kim

et al. 2009

The Journal of Immunology

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We determined the expression of the formyl peptide receptor (FPR) family and the functional roles of the FPR family in NK cells. All tested human NK cells express two members of the FPR family (FPR1 and FPR2). The expression of FPR3 was noted to occur in a donor-specific manner. The stimulation of NK cells with FPR family-selective agonists (fMLF (N-formyl-Met-Leu-Phe), MMK-1, F2L, and WKYMVm (Trp-Lys-Tyr-Met-Val-d-Met)) elicited cytolytic activity in resting NK cells, but not in IL-2-activated NK cells; the cytolytic activity was not inhibited by pertussis toxin. The FPR family agonists also stimulated chemotactic migration of IL-2-activated NK cells, but not resting NK cells; the chemotactic migration was completely inhibited by pertussis toxin. WKYMVm stimulates ERK, p38 MAPK, and JNK activities in both resting and IL-2-activated NK cells. WKYMVm-induced chemotactic migration was partially inhibited by PD98059 (2′-amino-3′-methoxyflavone); however, the inhibition of JNK by its selective inhibitor (SP600125, anthra[1,9-cd]pyrazol-6(2H)-one) dramatically inhibited the WKYMVm-induced cytolytic activity. Furthermore, WKYMVm-induced chemotactic migration and cytolytic activity were partly inhibited by FPR family-selective antagonists (cyclosporin H and WRWWWW). Taken together, our findings indicate that human NK cells express functional members of the FPR family, and in turn the activation of the three members of the FPR receptor family elicit cytolytic activity in NK cells, thus suggesting that the receptors are potentially important therapeutic targets for the modulation of NK cell-mediated immune responses.

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“…In addition, the FPR, FPR-like (FPRL)1, and FPRL2 are three members of the FPR family which have been reported in humans [8][9][10]. The activation of a member of the FPR family mediates the chemotactic migration of phagocytes.…”

Section: Introductionmentioning

confidence: 99%

F2L, a peptide derived from heme‐binding protein, inhibits LL‐37‐induced cell proliferation and tube formation in human umbilical vein endothelial cells

Lee

et al. 2007

FEBS Letters

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F2L, a peptide derived from heme-binding protein, was originally identified as an endogenous ligand for formyl peptide receptor-like (FPRL)2. Previously, we reported that F2L inhibits FPR and FPRL1-mediated signaling in neutrophils. Since endothelial cells express functional FPRL1, we examined the effect of F2L on LL-37 (an FPRL1 agonist)-induced signaling in human umbilical vein endothelial cells (HUVECs). F2L stimulated the chemotactic migration in HUVECs. However, F2L inhibited FPRL1 activity, resulting in the inhibition of cell proliferation and tube formation induced by LL-37 in HUVECs. We suggest that F2L will potentially be useful in the study of FPRL1 signaling and the development of drugs to treat diseases involving the FPRL1 in the vascular system.

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Receptors for chemotactic formyl peptides as pharmacological targets

Cited by 84 publications

References 106 publications

N-Terminal Residues of the Chemotaxis Inhibitory Protein of Staphylococcus aureus Are Essential for Blocking Formylated Peptide Receptor but Not C5a Receptor

N-Terminal Residues of the Chemotaxis Inhibitory Protein of Staphylococcus aureus Are Essential for Blocking Formylated Peptide Receptor but Not C5a Receptor

Functional Expression of Formyl Peptide Receptor Family in Human NK Cells

F2L, a peptide derived from heme‐binding protein, inhibits LL‐37‐induced cell proliferation and tube formation in human umbilical vein endothelial cells

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