Details

Autor(en) / Beteiligte

• Derian, Claudia K
• Solomon, Howard F
• Higgins, John D
• Beblavy, Michael J
• Santulli, Rosemary J
• Bridger, Gary J
• Pike, Marilyn C
• Kroon, Daniel J
• Fischman, Alan J

Titel

Selective Inhibition of N-Formylpeptide-Induced Neutrophil Activation by Carbamate-Modified Peptide Analogues

Ist Teil von

• Biochemistry (Easton), 1996-01, Vol.35 (4), p.1265-1269

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

1996

Quelle

MEDLINE

Beschreibungen/Notizen

• Stimulation of the leukocyte N-formylpeptide receptor (FPR) induces chemotaxis, cell adhesion, free radical release, and degranulation, responses associated with infection and inflammation. Under conditions where continuous activation of the receptor prevails, neutrophil-dependent tissue damage ensues. Antagonists of the FPR have potential for use as diagnostic and therapeutic agents. Hence, we have synthesized and evaluated a series of amino-terminal carbamate analogues of the peptide Met-Leu-Phe (MLF) in order to determine the structural requirements for imparting agonist or antagonist activity at the human neutrophil FPR. Peptides were evaluated in three in vitro assays:  receptor binding, superoxide anion release, and cell adhesion. Unbranched carbamates (methoxycarbonyl, ethoxycarbonyl, and n-butyloxycarbonyl) resulted in agonist activity, whereas branched carbamates (iso-butyloxycarbonyl, tert-butyloxycarbonyl, and benzyloxycarbonyl) were antagonists. The peptide antagonists were more potent inhibitors of superoxide anion release than cell adhesion by 4−7-fold. When iso-butyloxycarbonyl-MLF (i-Boc-MLF) was further modified at the carboxy terminus with Lys, antagonist potency was retained but without functional selectivity. Further C-terminal modification with the radionuclide linker diethylenetriaminepentaacetic acid did not alter the potency of i-Boc-MLFK. These results indicate that the switch from agonist to antagonist activity can be achieved by modifying the overall size and shape of the amino-terminal group; that modifications at both the amino and carboxy termini can alter the functional selectivity of the peptide; and that modifications can be tolerated at the carboxy terminus to allow for development of an antagonist for diagnostic applications.