C5a receptor antagonists

The anaphylatoxin C5a is an extremely potent proinflammatory peptide produc ed during activation of the complement system. The structure of C5a include s a 'core' region (N-terminal residues 1-63) consisting of four, antiparall el alpha helices held together by three disulfide linkages and a structured C-terminal 'tail' (residues 64-74). The C5a receptor belongs to the large class of seven transmembrane, G-protein-linked receptors. C5a appears to in teract with its receptor at two sites: the C5a core binds to the receptor's N-terminal extracellular domain while C5a's tail binds the receptor near A rg206, near the membrane surface of transmembrane helix V. C5a receptors ar e concentrated on blood granulocytes (neutrophils, eosinophils, and basophi ls) and tissue inflammatory cells (macrophages, mast cells, microglia); thu s the main effects of C5a are manifest as inflammation. Additionally, C5a r eceptors are also present, albeit in lower concentrations, on non-myeloid c ells, e.g. endothelial and smooth muscle cells where they may further influ ence inflammatory reactions such as blood cell emigration and tissue edema. C5a has been, implicated in myriad disorders, both acute and chronic; ther efore a C5a receptor antagonist is predicted to have utility as a therapeut ic agent. Unfortunately, few specific C5a receptor antagonists have been re ported, and only two have demonstrated activity in vivo. Furthermore, those reported are peptidic and hence have limited application therapeutically. The current state of C5a receptor antagonists is discussed as well as the p otential for their use against various human disorders. A Model of C5a rece ptor dimerization is presented to account for the high potency of the disul fide antagonist C5aRAD.