Selective inhibition of N-formylpeptide-induced neutrophil activation by carbamate-modified peptide analogues

Biochemistry. 1996 Jan 30;35(4):1265-9. doi: 10.1021/bi952087k.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Carbamates / chemistry*
  • Cell Adhesion / drug effects
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology
  • Humans
  • Molecular Sequence Data
  • N-Formylmethionine Leucyl-Phenylalanine / analogs & derivatives*
  • Neutrophil Activation / drug effects*
  • Neutrophils / physiology
  • Receptors, Formyl Peptide
  • Receptors, Immunologic / agonists*
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Immunologic / metabolism
  • Receptors, Peptide / agonists*
  • Receptors, Peptide / antagonists & inhibitors*
  • Receptors, Peptide / metabolism
  • Structure-Activity Relationship
  • Superoxides / metabolism


  • Carbamates
  • Receptors, Formyl Peptide
  • Receptors, Immunologic
  • Receptors, Peptide
  • Superoxides
  • N-Formylmethionine Leucyl-Phenylalanine