Compstatin is a 13-residue cyclic peptide (Ile1-Cys2-Val3-Val4-Gln5-Asp6-Trp7-Gly8-His9-His10-Arg11-Cys12-Thr13-NH2) discovered by phage-display random peptide libraty with C3b. C3b is an alternative pathway for proteolytic activation leading to covalent attachment of complement component to target cells, and it is also a fragment of complement component C3. The ring of compstatin is maintained by a disulphide bond between the two cysteines. Further studies on the substitution analogs and the solution structure of the peptide indicates that the type-1 β-turn segment of the peptide is critical for the preservation of its conformational stability and probably forms the C3 binding site.
From the studies of the mechanism of complement inhibition by Compstatin, it binds to native C3 and inhibits its cleavage by C3 convertase, and this inhibition was not caused by sterically hindered access to the C3a/C3b cleavage site. The backbone of Compstatin forms a type I β-turn comprising residues Gln5-Asp6-Trp7-Gly8, and Ala substitution analogs analysis reveals that in addition to Val3, type I β-turn residues (Gln5-Gly8) contribute significantly to the inhibitory activity of the peptide. In vivo test in primates, Compstatin can effectively inhibit complement activation, and this is a complete inhibition without adverse effects on heart rate or systemic arterial, central venous, and pulmonary arterial pressure.
The complement system is always activated through the classical/lectin (C4b, 2a) or alternative (C3b, Bb) pathways and provides the first line of defense against foreign pathogens, but its inappropriate activation has been a cause of tissue injury in many disease states. A variety of diseases, such as autoimmune diseases, acute respiratory distress syndrome, Alzheimer, stroke, heart attack, burn injuries, and reperfusion injuries are related to complement-mediated tissue injury, and it is also found to occur as a consequence of bioincompatibility situations, such as those encountered during dialysis and cardiopulmonary bypass and xenotransplantation. So, the specific complement inhibitors such as Compstatin need to be developed to deal with related diseases.
1. Sahu, A., Soulika, A. M., Morikis, D., Spruce, L., Moore, W. T., & Lambris, J. D. (2000). Binding kinetics, structure-activity relationship, and biotransformation of the complement inhibitor compstatin. The Journal of Immunology, 165(5), 2491-2499.
2. Nilsson, B., Larsson, R., Hong, J., Elgue, G., Ekdahl, K. N., Sahu, A., & Lambris, J. D. (1998). Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood, 92(5), 1661-1667.
3. Tamamis, P., Skourtis, S. S., Morikis, D., Lambris, J. D., & Archontis, G. (2007). Conformational analysis of compstatin analogues with molecular dynamics simulations in explicit water. Journal of Molecular Graphics and Modelling, 26(2), 571-580.