Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a

Activation of the human complement system of plasma proteins during immunol ogical host defense can result in overproduction of potent proinflammatory peptides such as the anaphylatoxin C5a. Excessive levels of C5a are associa ted with numerous immunoinflammatory diseases, but there is as yet no clini cally available antagonist to regulate the effects of C5a. We now describe a series of small molecules derived from the C-terminus of C5a, some of whi ch are the most potent low-molecular-weight C5a receptor antagonists report ed to date for the human polymorphonuclear leukocyte (PMN) C5a receptor. H- 1 NMR spectroscopy was used to determine solution structures for two cyclic antagonists and to indicate that antagonism is related to a turn conformat ion, which can be stabilized in cyclic molecules that are preorganized for receptor binding. While several cyclic derivatives were of similar antagoni stic potency, the most potent antagonist was a hexapeptide-derived macrocyc le AcF[OPdChaWR] with an IC50 = 20 nM against a maximal concentration of C5 a (100 nM) on intact human PMNs. Such potent C5a antagonists may be useful probes to investigate the role of C5a in host defenses and to develop thera peutic agents for the treatment of many currently intractable inflammatory conditions.