Development of C5a receptor antagonists. Differential loss of functional responses

J Immunol. 1994 Nov 1;153(9):4200-5.


C5a is a 74-amino acid glycoprotein generated on activation of the C system. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antagonist would be of considerable therapeutic importance. However, efforts at generating antagonists have so far been unsuccessful. Structure/activity studies of the C terminus of C5a have generated peptide analogues with nanomolar affinities, but all of these retain strong agonist properties. We now report hexapeptides of the form NMePhe-Lys-Pro-dCha-X-dArg in which increasing aromaticity at position 5 leads to a progressive loss of agonism with little change in binding affinity. The different responses induced by C5a are lost in the order: degranulation before Ca(2+)-flux before chemotaxis. We also describe the first full antagonist of C5a, because the peptide in which x = Trp is not only devoid of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated G protein activation.

MeSH terms

  • Amino Acid Sequence
  • Calcium / metabolism
  • Cell Degranulation / physiology
  • Chemotaxis, Leukocyte / physiology
  • Complement C5a / agonists
  • Complement C5a / antagonists & inhibitors
  • Complement C5a / chemistry*
  • Complement C5a / metabolism*
  • Flow Cytometry
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Molecular Sequence Data
  • Neutrophils / metabolism
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / pharmacology
  • Peroxidase / metabolism
  • Protein Binding


  • Peptide Fragments
  • Complement C5a
  • Peroxidase
  • GTP Phosphohydrolases
  • Calcium