title: Compstatin: a complement inhibitor on its way to clinical application.
abstract: Therapeutic 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ricklin@mail.med.upenn.edu
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
mesh_terms: D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D002986:Clinical Trials as Topic; D003176:Complement C3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005544:Forecasting; D006801:Humans; D020128:Inhibitory Concentration 50; D008268:Macular Degeneration / Q000188:drug therapy; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: D003176:Complement C3; D003169:Complement Inactivator Proteins; D010456:Peptides, Cyclic; C111828:compstatin; D000409:Alanine