| Abstract
| - Activation of the human complement system of plasma proteins during immunological hostdefense can result in overproduction of potent proinflammatory peptides such as the anaphylatoxin C5a. Excessive levels of C5a are associated with numerous immunoinflammatorydiseases, but there is as yet no clinically 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 whichare the most potent low-molecular-weight C5a receptor antagonists reported to date for thehuman polymorphonuclear leukocyte (PMN) C5a receptor. 1H NMR spectroscopy was used todetermine solution structures for two cyclic antagonists and to indicate that antagonism isrelated to a turn conformation, which can be stabilized in cyclic molecules that are preorganizedfor receptor binding. While several cyclic derivatives were of similar antagonistic potency, themost potent antagonist was a hexapeptide-derived macrocycle AcF[OPdChaWR] with an IC50= 20 nM against a maximal concentration of C5a (100 nM) on intact human PMNs. Such potentC5a antagonists may be useful probes to investigate the role of C5a in host defenses and todevelop therapeutic agents for the treatment of many currently intractable inflammatoryconditions.
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