DECAPEPTIDE AGONISTS OF HUMAN C5A - THE RELATIONSHIP BETWEEN CONFORMATION AND NEUTROPHIL RESPONSE

A series of decapeptide analogues corresponding to the C-terminal regi on of the human C5a anaphylatoxin (C5a(65-74)) was synthesized with re sidue substitutions to restrict conformational flexibility in the C-te rminal region (residues 71-74). These analogues behaved as full agonis ts of natural C5a in their ability to induce shape change (polarizatio n) and the release of enzyme (beta-glucuronidase) from human neutrophi ls (PMNs). There was a significant pharmacological correlation between the polarization and enzyme-release assays, suggesting similarities i n PMN responsiveness toward these constrained peptides. Good correlati ons were also observed between these two PMN responses and spasmogenic activity (smooth muscle contraction of human fetal artery). A structu re-function analysis for PMN polarization and enzyme release led to th e identification of the following preferred backbone conformations: a twisted, helixlike conformation for residues 65-69, an extended confor mation for residues 70-71, and a beta-turn of type V for residues (71) 72-74. The existence of a C-terminal, type V beta-turn is supported by the NOE (nuclear Overhauser effect) results of two peptides from this series. These conformational features are reminiscent of those that w ere shown to correlate with the expression of spasmogenic and platelet aggregatory activities in an earlier investigation (Sanderson, S. D.; et al. J. Med. Chem. 1994, 37, 3171). These results suggest that PMNs and the cells responsible for smooth muscle contraction possess C5a r eceptors that respond to similar topochemical features presented by th e agonist peptide ligand.