DECAPEPTIDE AGONISTS OF HUMAN C5A - THE RELATIONSHIP BETWEEN CONFORMATION AND SPASMOGENIC AND PLATELET AGGREGATORY ACTIVITIES

A series of decapeptide analogues corresponding to the C-terminal regi on of human C5a anaphylatoxin (C5a(65-74)) was synthesized with residu e substitutions to restrict conformational flexibility in the C-termin us. These conformationally constrained peptides behaved as agonists of C5a in spasmogenic assays (smooth muscle contraction in human fetal a rtery, guinea pig ileum, and guinea pig lung parenchyma) as well as gu inea pig platelet aggregation. There were significant correlations in the potencies of these peptides between the various assays. A structur e-function analysis led to the identification of a preferred backbone conformation that correlated with the expression of these biological r esponses. These backbone structural motifs were consistent with a heli x-like conformation for residues 65-69, an elongated structure for res idues 70-71, and a beta-turn of either type II or type V for residues (71)72-74. The most potent of these agonists expressed almost 5% of th e potency of natural C5a.