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Compstatin: a complement inhibitor on its way to clinical application Ricklin D; Lambris JDAdv Exp Med Biol 2008[]; 632 (ä): 273-92Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic.|Alanine/metabolism[MESH]|Amino Acid Sequence[MESH]|Amino Acid Substitution[MESH]|Binding Sites[MESH]|Clinical Trials as Topic[MESH]|Complement C3/*antagonists & inhibitors/metabolism[MESH]|Complement Inactivator Proteins/*pharmacology[MESH]|Escherichia coli/genetics[MESH]|Forecasting[MESH]|Humans[MESH]|Inhibitory Concentration 50[MESH]|Macular Degeneration/drug therapy[MESH]|Models, Biological[MESH]|Models, Chemical[MESH]|Models, Molecular[MESH]|Molecular Sequence Data[MESH]|Peptides, Cyclic/chemistry/genetics/*pharmacology/*therapeutic use[MESH]|Protein Binding[MESH]|Protein Conformation[MESH]|Protein Structure, Secondary[MESH] |
