Low-Molecular-Weight Peptidic and Cyclic Antagonists of the Receptor for the Complement Factor C5a

Abstract

Activation of the human complement system of plasma proteins during immunological host defense can result in overproduction of potent proinflammatory peptides such as the anaphylatoxin C5a. Excessive levels of C5a are associated with numerous immunoinflammatory diseases, 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 which are the most potent low-molecular-weight C5a receptor antagonists reported to date for the human polymorphonuclear leukocyte (PMN) C5a receptor. 1H NMR spectroscopy was used to determine solution structures for two cyclic antagonists and to indicate that antagonism is related to a turn conformation, which can be stabilized in cyclic molecules that are preorganized for receptor binding. While several cyclic derivatives were of similar antagonistic potency, the most 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 potent C5a antagonists may be useful probes to investigate the role of C5a in host defenses and to develop therapeutic agents for the treatment of many currently intractable inflammatory conditions.

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

“…6A). The maximum effect of MAP-C5a was observed at a concentration of 10 Ϫ8 M. Moreover, this protective effect of MAP-C5a was prevented by pretreatment of DIV 4 granule neurons with the C5aR antagonist (10 Ϫ7 M)-derived macrocycle AcPhe(L-ornithine-Pro-D-cyclohexylalanine-Trp-Arg) (44) (Fig. 6A).…”

Identification of a Potent and Orally Active Non-peptide C5a Receptor Antagonist

“…Mongolian gerbils (MGS/Sea), Hartley guinea pigs (Std), rabbits (KBT JW), and beagle dogs were purchased from Seac Yoshitomi (Fukuoka, Japan), Japan SLC (Shizuoka, Japan), Biotec (Saga, Japan), and Keari (Osaka, Japan), respectively. (31).…”

Comparative Agonist/Antagonist Responses in Mutant Human C5a Receptors Define the Ligand Binding Site

“…The receptors were prepared for docking by assigning charges and potentials and adjusting the side chains of specific residues where necessary (Asp ). The ligands used were based on the NMR structures that we have previously published and refined (21) for the cyclic and acyclic antagonists (17,21). Docking studies were carried out using Gold Versions 2.1, and results were viewed using InsightII.…”