The proinflammatory activity of the anaphylatoxin C5a is the driving force behind many complement associated disorders. After its liberation from C5, this hormone-like glycoprotein binds to two high-affinity receptors, the C5a receptor (C5aR) and C5L2. Most of the proinflammatory signaling seems to be induced by C5aR, a G-protein-coupled receptor that is expressed on numerous myeloid (e.g., neutrophils, macrophages) and nonmyeloid cells. Despite its similar structure and affinity for C5a, the C5L2 receptor produces a completely different signaling pattern. In plasma, the activity of C5a is controlled through the removal of the C-terminal arginyl residue by the plasma enzyme carboxypeptidase N.
Selective inhibition of the binding of C5a to its receptors offers a very promising opportunity for dampening the inflammatory response without depleting the defensive potential of complement. The macromolecular biopharmaceuticals either inhibit C5a generation (anti-C5 antibodies and aptamers) or neutralize the C5a-C5aR interaction by shielding the relevant binding site. C5aR antagonists, on the other hand, are designed to bind to the receptor with high affinity without inducing any signaling activity. Because only one of the two proposed binding sites on C5aR has to be targeted for this purpose, these antagonists are expected to be rather small. Simultaneous efforts by many companies have focused on reducing the functional fragment of C5a to a C-terminal hexapeptide, while replacing individual residues to shift its activity from agonistic to antagonistic. Cyclization of these hexapeptides not only allows them to be locked into the desired turnconformation but also gives them higher stability with regard to proteolytic degradation.
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