N-Terminus Urea-Substituted Chemotactic Peptides:  New Potent Agonists and Antagonists toward the Neutrophil fMLF Receptor

Higgins, John; Bridger, Gary; Derian, Claudia K.; Beblavy, Michael J.; Hernández, Paola; Gaul, Forrest E.; Abrams, Matthew; Pike, Marilyn C.; Solomon, Howard F.

doi:10.1021/jm950908d

Cited by 48 publications

(22 citation statements)

References 10 publications

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“…This is true for N-ureido substituents such as methyl-, ethyl-, n-propyl-, iso-butyl-, tert-butyl-and benzylureido [82]. Moreover, it has been reported that N-ureidoPhe-D-Leu-Phe-D-Leu-Phe peptide derivatives, Fig.…”

Section: Formylpeptide Receptor Antagonistsmentioning

confidence: 91%

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Studies on Human Neutrophil Biological Functions by Means of Formylpeptide Receptor Agonists and Antagonists

Dalpiaz

Spisani

Biondi

et al. 2003

CDTIEMD

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Phagocytes are activated by several extracellular signals, including formyl-peptides derived from bacterial proteins or disrupted cells. The most intensely studied member of the formylpeptide family is the synthetic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), whose specific receptors have been identified on neutrophil plasma membrane and subsequently cloned. The fMLP-receptor interaction activates multiple transduction pathways responsible for various neutrophil functions such as adhesion, chemotaxis, exocytosis of secretory granules and superoxide anion production, which represent the physiological response to bacterial infection and tissue damage. An unresolved question is whether signaling requirements are identical or specific for each physiological function. The development of fMLP receptor agonists and antagonists has led to an improvement of our knowledge about the above issue. Of particular interest is the possibility that receptorial antagonists, able to transiently inhibit neutrophil responses to formylpeptides, could be therapeutic agents in the treatment of inflammation-related diseases. Aim of this review is, i) to summarise the current understanding of the series of events that begins at the level of formylpeptide-receptor interaction and is responsible for the activation of transduction pathways, which finally determine neutrophil response; ii) to define the state of art regarding the synthesis as well as the biological actions of fMLP receptor agonists and antagonists.

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Section: Formylpeptide Receptor Antagonistsmentioning

confidence: 91%

“…Moreover, it has been reported that N-ureidoPhe-D-Leu-Phe-D-Leu-Phe peptide derivatives, Fig. (4C) and (4D), show an enhanced FPR affinity and antagonist power on human neutrophils, with respect to the tripeptide MLP homologs [82].…”

Section: Formylpeptide Receptor Antagonistsmentioning

confidence: 95%

Studies on Human Neutrophil Biological Functions by Means of Formylpeptide Receptor Agonists and Antagonists

Dalpiaz

Spisani

Biondi

et al. 2003

CDTIEMD

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“…FPR binds bacterial N-formylated peptides, such as fMLF, which is the prototypic formylated peptide purified from Escherichia coli cultures (2). More recently, certain nonformylated peptides have been observed to bind to and activate neutrophils through FPR (3)(4)(5)(6)(7).…”

mentioning

confidence: 99%

Experimental Evidence for Lack of Homodimerization of the G Protein-Coupled Human N-Formyl Peptide Receptor

Gripentrog

Kantele

Jesaitis

et al. 2003

The Journal of Immunology

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A large number of G protein-coupled receptors have been shown to form homodimers based on a number of different techniques such as receptor coimmunoprecipitation, cross-linking, and fluorescence resonance energy transfer. In addition, functional assays of cells coexpressing a mutant receptor with a wild-type receptor have shown receptor phenotypes that can best be explained through dimerization. We asked whether the human neutrophil N-formyl peptide receptor (FPR) forms dimers in Chinese hamster ovary cells by coexpressing wild-type FPR with one of two mutants: D71A, which is uncoupled from G protein, and N297A, which has a defect in receptor phosphorylation and endocytosis. Experiments measuring chemotaxis, ligand-induced release of intracellular calcium, and p42/44 mitogen-activated protein kinase activation did not show an inhibitory effect of the coexpressed FPR D71A mutant. Coexpressed wild-type receptor was efficiently internalized, but failed to correct the endocytosis defects of the D71A and the N297A mutants. To explore the possibility that the mutations themselves prevented dimerization, we examined the coimmunoprecipitation of differentially epitope-tagged FPR. Immunoprecipitation of hemagglutinin-tagged FPR failed to coimmunoprecipitate coexpressed c-myc-tagged FPR and vice versa. Together, these data suggest that, unlike many other G protein-coupled receptors, FPR does not form homodimers.

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“…Recent findings indicate that a key structural feature, involved in the modulation of agonistic and antagonistic activity of chemotactic formyl peptides, resides in the overall size and chemical nature of the substituent bound at the N‐terminal amino group which, in the prototypical ligand, is constituted by the formylic H‐CO group. In particular, it has been well established that N ‐formylation does not represent an absolute requirement for activity; both carbamate and urea functionalities, replacing the native formamido group, can in fact originate selective or highly active ligands (1–3). It should be noted, however, that findings concerning the biochemical consequences of chemical modifications at the N‐terminus of chemotactic oligopeptides are just emerging in the literature and only relatively few results, on the wide range of analogs studied to date, deal with alterations performed at the N‐terminal formamido group (3).…”

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confidence: 99%

“…1 by examining new derivatives characterized by the presence, at the N‐terminal nitrogen atom, of an aromatic substituent. This type of structure was considered appropriate in light of the striking recent observation that highly active non‐ N ‐formyl MLF analogs can be obtained by replacing the formylic group with a N‐terminal ureido moiety bearing an aromatic ring at the nitrogen atom (3). Thus, we report here results concerning 2‐hydrazonoacyl derivatives in which a p ‐chlorophenyl ( p ‐Cl‐C 6 H 4 ‐) substituent (compounds 2 and 3 ) and a p ‐toluoyl ( p ‐CH 3 ‐C 6 H 4 ‐CO‐) substituent (compound 4 ) replace the formylic H‐CO‐ (Fig.…”

mentioning

confidence: 99%

Pseudopeptides containing the 2‐hydrazonoacyl fragment: analogs of the chemotactic agent HCO‐Met‐Leu‐Phe‐OMe

Torrini

Nalli

Paradisi

et al. 2001

The Journal of Peptide Research

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In order to further examine the properties of pseudopeptides containing the 2-hydrazonoacyl fragment, two new series of analogs of the prototypical chemotactic N-formyl-tripeptide HCO-Met-Leu-Phe-OMe were designed and synthesized. The first group contains the new fragment as the N-terminal residue and is represented by the N-aryl derivatives p-Cl-C6H4-NH-N=C(R)-CO-Leu-Phe-OMe (2 and 3) and by the corresponding N-aroyl analogs p-CH3-C6H4-CO-NH-N=C(R)-CO-Leu-Phe-OMe (4). The second group contains the new fragment in place of the central Leu residue and is represented by compounds HCO-Xaa-NH-N=C(R)-CO-Phe-OMe (7a and 7b) where Xaa is Nle and Met, respectively. The conformational and biochemical properties of the new products were examined.

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N-Terminus Urea-Substituted Chemotactic Peptides: New Potent Agonists and Antagonists toward the Neutrophil fMLF Receptor

Cited by 48 publications

References 10 publications

Studies on Human Neutrophil Biological Functions by Means of Formylpeptide Receptor Agonists and Antagonists

Studies on Human Neutrophil Biological Functions by Means of Formylpeptide Receptor Agonists and Antagonists

Experimental Evidence for Lack of Homodimerization of the G Protein-Coupled Human N-Formyl Peptide Receptor

Pseudopeptides containing the 2‐hydrazonoacyl fragment: analogs of the chemotactic agent HCO‐Met‐Leu‐Phe‐OMe

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