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

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• 作者：Claudia K. Derian ; Howard F. Solomon ; John D. Higgins ; III ; Michael J. Beblavy ; Rosemary J. Santulli ; Gary J. Bridger ; Marilyn C. Pike ; Daniel J. Kroon ; and Alan J. Fischman
• 刊名：Biochemistry
• 出版年：1996
• 出版时间：January 30, 1996
• 年：1996
• 卷：35
• 期：4
• 页码：1265 - 1269
• 全文大小：272K
• 年卷期：v.35,no.4(January 30, 1996)
• ISSN：1520-4995

文摘

Stimulation of the leukocyte N-formylpeptide receptor(FPR) induces chemotaxis, cell adhesion,free radical release, and degranulation, responses associated withinfection and inflammation. Underconditions where continuous activation of the receptor prevails,neutrophil-dependent tissue damage ensues.Antagonists of the FPR have potential for use as diagnostic andtherapeutic agents. Hence, we havesynthesized and evaluated a series of amino-terminal carbamateanalogues of the peptide Met-Leu-Phe(MLF) in order to determine the structural requirements for impartingagonist or antagonist activity at thehuman neutrophil FPR. Peptides were evaluated in three invitro assays: receptor binding, superoxideanion release, and cell adhesion. Unbranched carbamates(methoxycarbonyl, ethoxycarbonyl, andn-butyloxycarbonyl) resulted in agonist activity, whereasbranched carbamates (iso-butyloxycarbonyl,tert-butyloxycarbonyl, and benzyloxycarbonyl) were antagonists. Thepeptide antagonists were more potentinhibitors of superoxide anion release than cell adhesion by4-7-fold. When iso-butyloxycarbonyl-MLF(i-Boc-MLF) was further modified at the carboxy terminuswith Lys, antagonist potency was retained butwithout functional selectivity. Further C-terminal modificationwith the radionuclide linker diethylenetriaminepentaacetic acid did not alter the potency ofi-Boc-MLFK. These results indicate that theswitchfrom agonist to antagonist activity can be achieved by modifying theoverall size and shape of the amino-terminal group; that modifications at both the amino and carboxy terminican alter the functional selectivityof the peptide; and that modifications can be tolerated at the carboxyterminus to allow for developmentof an antagonist for diagnostic applications.