DEVELOPMENT OF C5A RECEPTOR ANTAGONISTS - DIFFERENTIAL LOSS OF FUNCTIONAL-RESPONSES

C5a is a 74-amino acid glycoprotein generated on activation of the C s ystem. The responses evoked by C5a, both in vitro and in vivo, and its association with inflammatory diseases, suggest that a receptor antag onist would be of considerable therapeutic importance. However, effort s at generating antagonists have so far been unsuccessful. Structure/a ctivity studies of the C terminus of C5a have generated peptide analog ues 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 progr essive loss of agonism with little change in binding affinity. The dif ferent responses induced by C5a are lost in the order: degranulation b efore Ca2+-flux before chemotaxis. We also describe the first full ant agonist of C5a, because the peptide in which x = Trp is not only devoi d of all agonist properties, but it inhibits C5a induced degranulation and C5a stimulated C protein activation.