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.
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References
Andersson, J., Ekdahl, K.N., Lambris, J.D. and Nilsson, B. (2005) Binding of C3 fragments on top of adsorbed plasma proteins during complement activation on a model biomaterial surface. Biomaterials 26, 1477–1485
Blick, S.K., Keating, G.M. and Wagstaff, A.J. (2007) Ranibizumab. Drugs 67, 1199–1206; discussion 1207–1199
Cavarocchi, N.C., Schaff, H.V., Orszulak, T.A., Homburger, H.A., Schnell, W.A., Jr. and Pluth, J.R. (1985) Evidence for complement activation by protamine-heparin interaction after cardiopulmonary bypass. Surgery 98, 525–531
Davis, A.E.III, (2006) Mechanism of angioedema in first complement component inhibitor deficiency. Immunol. Allergy Clin. North Am. 26, 633–651
Degn, S.E., Thiel, S. and Jensenius, J.C. (2007) New perspectives on mannan-binding lectin-mediated complement activation. Immunobiology 212, 301–311
Fiane, A.E., Mollnes, T.E., Videm, V., Hovig, T., Hogasen, K., Mellbye, O.J., Spruce, L., Moore, W.T., Sahu, A. and Lambris, J.D. (1999a) Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts. Xenotransplantation 6, 52–65
Fiane, A.E., Mollnes, T.E., Videm, V., Hovig, T., Hogasen, K., Mellbye, O.J., Spruce, L., Moore, W.T., Sahu, A. and Lambris, J.D. (1999b) Prolongation of ex vivo-perfused pig xenograft survival by the complement inhibitor compstatin. Transplant. Proc. 31, 934–935
Furlong, S.T., Dutta, A.S., Coath, M.M., Gormley, J.J., Hubbs, S.J., Lloyd, D., Mauger, R.C., Strimpler, A.M., Sylvester, M.A., Scott, C.W. and Edwards, P.D. (2000) C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl alpha-ketoheterocycles. Immunopharmacology 48, 199–212
Gronroos, J.O., Salonen, J.H., Viander, M., Nevalainen, T.J. and Laine, V.J. (2005) Roles of group IIA phospholipase A2 and complement in killing of bacteria by acute phase serum. Scand. J. Immunol. 62, 413–419
Hammel, M., Sfyroera, G., Pyrpassopoulos, S., Ricklin, D., Ramyar, K.X., Pop, M., Jin, Z., Lambris, J.D. and Geisbrecht, B.V. (2007a) Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus. J. Biol. Chem. 282, 30051–30061
Hammel, M., Sfyroera, G., Ricklin, D., Magotti, P., Lambris, J.D. and Geisbrecht, B.V. (2007b) A structural basis for complement inhibition by Staphylococcus aureus. Nat. Immunol. 8, 430–437
Holland, M.C., Morikis, D. and Lambris, J.D. (2004) Synthetic small-molecule complement inhibitors. Curr. Opin. Investig. Drugs 5, 1164–1173
Janssen, B.J. and Gros, P. (2007) Structural insights into the central complement component C3. Mol. Immunol. 44, 3–10
Janssen, B.J., Christodoulidou, A., McCarthy, A., Lambris, J.D. and Gros, P. (2006) Structure of C3b reveals conformational changes that underlie complement activity. Nature 444, 213–216
Janssen, B.J., Halff, E.F., Lambris, J.D. and Gros, P. (2007) Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. J. Biol. Chem. 282, 29241–29247
Jha, P., Bora, P.S. and Bora, N.S. (2007) The role of complement system in ocular diseases including uveitis and macular degeneration. Mol. Immunol. 44, 3901–3908
Jongerius, I., Kohl, J., Pandey, M.K., Ruyken, M., van Kessel, K.P., van Strijp, J.A. and Rooijakkers, S.H. (2007) Staphylococcal complement evasion by various convertase-blocking molecules. J. Exp. Med. 204, 2461–2471
Katragadda, M. and Lambris, J.D. (2006) Expression of compstatin in Escherichia coli. : incorporation of unnatural amino acids enhances its activity Protein Expr. Purif. 47, 289–295
Katragadda, M., Morikis, D. and Lambris, J.D. (2004) Thermodynamic studies on the interaction of the third complement component and its inhibitor, compstatin. J. Biol. Chem. 279, 54987–54995
Katragadda, M., Magotti, P., Sfyroera, G. and Lambris, J.D. (2006) Hydrophobic effect and hydrogen bonds account for the improved activity of a complement inhibitor, compstatin. J. Med. Chem. 49, 4616–4622
Katschke, K.J., Jr., Helmy, K.Y., Steffek, M., Xi, H., Yin, J., Lee, W.P., Gribling, P., Barck, K.H., Carano, R.A., Taylor, R.E., Rangell, L., Diehl, L., Hass, P.E., Wiesmann, C. and van Lookeren Campagne, M. (2007) A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis. J. Exp. Med. 204, 1319–1325
Kay, B.K., Kasanov, J. and Yamabhai, M. (2001) Screening phage-displayed combinatorial peptide libraries. Methods 24, 240–246
Kee, K.S. and Jois, S.D. (2003) Design of beta-turn based therapeutic agents. Curr. Pharm. Des. 9, 1209–1224
Klegeris, A., Singh, E.A. and McGeer, P.L. (2002) Effects of C-reactive protein and pentosan polysulphate on human complement activation. Immunology 106, 381–388
Klepeis , J.L., Floudas, C.A., Morikis, D., Tsokos, C.G., Argyropoulos, E., Spruce, L. and Lambris, J.D. (2003) Integrated computational and experimental approach for lead optimization and design of compstatin variants with improved activity. J. Am. Chem. Soc. 125, 8422–8423
Klepeis, J.L., Floudas, C.A., Morikis, D., Tsokos, C.G. and Lambris, J.D. (2004) Design of peptide analogues with improves activity using a novel de novo protein design approach. Ind. Eng. Chem. Res. 43, 3817–3826
Ladner, R.C., Sato, A.K., Gorzelany, J. and de Souza, M. (2004) Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov. Today 9, 525–529
Lambris, J.D. and Holers, V.M. (Eds.) (2000) Therapeutic Interventions in the Complement System. Humana Press, Totowa, NJ, USA
Lambris, J.D., Ricklin, D. and Geisbrecht, B.V. (2008) Complement evasion by human pathogens. Nat. Rev. Microbiol. 6, 132–142
Lappegard, K.T., Fung, M., Bergseth, G., Riesenfeld, J., Lambris, J.D., Videm, V. and Mollnes, T.E. (2004) Effect of complement inhibition and heparin coating on artificial surface-induced leukocyte and platelet activation. Ann. Thorac. Surg. 77, 932–941
Lappegard, K.T., Riesenfeld, J., Brekke, O.L., Bergseth, G., Lambris, J.D. and Mollnes, T.E. (2005) Differential effect of heparin coating and complement inhibition on artificial surface-induced eicosanoid production. Ann. Thorac. Surg. 79, 917–923
Lappegard , K.T., Bergseth, G., Riesenfeld, J., Pharo, A., Magotti, P., Lambris, J.D. and Mollnes, T.E. (2007) The artificial surface-induced whole blood inflammatory reaction revealed by increases in a series of chemokines and growth factors is largely complement dependent. J. Biomed. Mater. Res. A
Mallik, B. and Morikis, D. (2005) Development of a quasi-dynamic pharmacophore model for anti-complement peptide analogues. J. Am. Chem. Soc. 127, 10967–10976
Mallik, B., Lambris, J.D. and Morikis, D. (2003) Conformational interconversion in compstatin probed with molecular dynamics simulations. Proteins 53, 130–141
Mallik, B., Katragadda, M., Spruce, L.A., Carafides, C., Tsokos, C.G., Morikis, D. and Lambris, J.D. (2005) Design and NMR characterization of active analogues of compstatin containing non-natural amino acids. J. Med. Chem. 48, 274–286
Markiewski, M.M. and Lambris, J.D. (2007) The role of complement in inflammatory diseases from behind the scenes into the spotlight. Am. J. Pathol. 171, 715–727
Mollnes, T.E., Brekke, O.L., Fung, M., Fure, H., Christiansen, D., Bergseth, G., Videm, V., Lappegard, K.T., Kohl, J. and Lambris, J.D. (2002) Essential role of the C5a receptor in E. coli. -induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation Blood 100, 1869–1877
Morikis, D. and Lambris, J.D. (2002) Structural aspects and design of low-molecular-mass complement inhibitors. Biochem. Soc. Trans. 30, 1026–1036
Morikis, D., Assa-Munt, N., Sahu, A. and Lambris, J.D. (1998) Solution structure of compstatin, a potent complement inhibitor. Protein Sci. 7, 619–627
Morikis, D., Roy, M., Sahu, A., Troganis, A., Jennings, P.A., Tsokos, G.C. and Lambris, J.D. (2002) The structural basis of compstatin activity examined by structure-function-based design of peptide analogs and NMR. J. Biol. Chem. 277, 14942–14953
Morikis, D., Soulika, A.M., Mallik, B., Klepeis, J.L., Floudas, C.A. and Lambris, J.D. (2004) Improvement of the anti-C3 activity of compstatin using rational and combinatorial approaches. Biochem. Soc. Trans. 32, 28–32
Mulakala, C., Lambris, J.D. and Kaznessis, Y. (2007) A simple, yet highly accurate, QSAR model captures the complement inhibitory activity of compstatin. Bioorg. Med. Chem. 15, 1638–1644
Nielsen, E.W., Waage, C., Fure, H., Brekke, O.L., Sfyroera, G., Lambris, J.D. and Mollnes, T.E. (2007) Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement. Mol. Immunol. 44, 1819–1826
Nilsson, B., Larsson, R., Hong, J., Elgue, G., Ekdahl, K.N., Sahu, A. and Lambris, J.D. (1998) Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation. Blood 92, 1661–1667
Nilsson, B., Ekdahl, K.N., Mollnes, T.E. and Lambris, J.D. (2007) The role of complement in biomaterial-induced inflammation. Mol. Immunol. 44, 82–94
Pedersen, E.D., Aass, H.C., Rootwelt, T., Fung, M., Lambris, J.D. and Mollnes, T.E. (2007) CD59 efficiently protects human NT2-N neurons against complement-mediated damage. Scand. J. Immunol. 66, 345–351
Petrukhin, K. (2007) New therapeutic targets in atrophic age-related macular degeneration. Expert Opin. Ther. Targets 11, 625–639
Potentia (2006) Press Release: Potentia Pharmaceuticals Licences Complement Inhibitor Compstatin from the University of Pennsylvania (http://www.potentiapharma.com/ about/ news.htm#13)
Potentia (2007) Press Release: Potentia Pharmaceuticals Announces Initiation of Phase I Clinical Trials to Evaluate its Lead Compound for Age-Related Macular Degeneration (http://www.potentiapharma.com/about/news.htm#17(
Ricklin, D. and Lambris, J.D. (2007a) Complement-targeted therapeutics. Nat. Biotechnol. 25, 1265–1275
Ricklin, D. and Lambris, J.D. (2007b) Exploring the complement interaction network using surface plasmon resonance. Adv. Exp. Med. Biol. 598, 260–278
Ritis, K., Doumas, M., Mastellos, D., Micheli, A., Giaglis, S., Magotti, P., Rafail, S., Kartalis, G., Sideras, P. and Lambris, J.D. (2006) A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802
Rother, R.P., Rollins, S.A., Mojcik, C.F., Brodsky, R.A. and Bell, L. (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256–1264
Rotondi, K.S. and Gierasch, L.M. (2006) Natural polypeptide scaffolds: beta-sheets, beta-turns, and beta-hairpins. Biopolymers 84, 13–22
Sahu, A., Kay, B.K. and Lambris, J.D. (1996) Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J. Immunol. 157, 884–891
Sahu, A., Sunyer, J.O., Moore, W.T., Sarrias, M.R., Soulika, A.M. and Lambris, J.D. (1998) Structure, functions, and evolution of the third complement component and viral molecular mimicry. Immunol. Res. 17, 109–121
Sahu, A., Soulika, A.M., Morikis, D., Spruce, L., Moore, W.T. and Lambris, J.D. (2000) Binding kinetics, structure-activity relationship, and biotransformation of the complement inhibitor compstatin. J. Immunol. 165, 2491–2499
Sahu, A., Morikis, D. and Lambris, J.D. (2003) Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3. Mol. Immunol. 39, 557–566
Sarrias, M.R., Whitbeck, J.C., Rooney, I., Spruce, L., Kay, B.K., Montgomery, R.I., Spear, P.G., Ware, C.F., Eisenberg, R.J., Cohen, G.H. and Lambris, J.D. (1999) Inhibition of herpes simplex virus gD and lymphotoxin-alpha binding to HveA by peptide antagonists. J. Virol. 73, 5681–5687
Sato, A.K., Viswanathan, M., Kent, R.B. and Wood, C.R. (2006) Therapeutic peptides: technological advances driving peptides into development. Curr. Opin. Biotechnol. 17, 638–642
Schmidt, S., Haase, G., Csomor, E., Lutticken, R. and Peltroche-Llacsahuanga, H. (2003) Inhibitor of complement, compstatin, prevents polymer-mediated Mac-1 up-regulation of human neutrophils independent of biomaterial type tested. J. Biomed. Mater. Res. A 66, 491–499
Solvik, U.O., Haraldsen, G., Fiane, A.E., Boretti, E., Lambris, J.D., Fung, M., Thorsby, E. and Mollnes, T.E. (2001) Human serum-induced expression of E-selectin on porcine aortic endothelial cells in vitro is totally complement mediated. Transplantation 72, 1967–1973
Song, M.K., Kim, S.Y. and Lee, J. (2005) Understanding the structural characteristics of compstatin by conformational space annealing. Biophys. Chem. 115, 201–207
Soulika, A.M., Khan, M.M., Hattori, T., Bowen, F.W., Richardson, B.A., Hack, C.E., Sahu, A., Edmunds, L.H., Jr. and Lambris, J.D. (2000) Inhibition of heparin/protamine complex-induced complement activation by compstatin in baboons. Clin. Immunol. 96, 212–221
Soulika, A.M., Morikis, D., Sarrias, M.R., Roy, M., Spruce, L.A., Sahu, A. and Lambris, J.D. (2003) Studies of structure-activity relations of complement inhibitor compstatin. J. Immunol. 171, 1881–1890
Soulika, A.M., Holland, M.C., Sfyroera, G., Sahu, A. and Lambris, J.D. (2006) Compstatin inhibits complement activation by binding to the beta-chain of complement factor 3. Mol. Immunol. 43, 2023–2029
Tamamis, P., Skourtis, S.S., Morikis, D., Lambris, J.D. and Archontis, G. (2007) Conformational analysis of compstatin analogues with molecular dynamics simulations in explicit water. J. Mol. Graph. Model. 26, 571–580
Tejde, A., Mathsson, L., Ekdahl, K.N., Nilsson, B. and Ronnelid, J. (2004) Immune complex-stimulated production of interleukin-12 in peripheral blood mononuclear cells is regulated by the complement system. Clin. Exp. Immunol. 137, 521–528
Wells, J.A. and McClendon, C.L. (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450, 1001–1009
Wiesmann, C., Katschke, K.J., Yin, J., Helmy, K.Y., Steffek, M., Fairbrother, W.J., McCallum, S.A., Embuscado, L., DeForge, L., Hass, P.E. and van Lookeren Campagne, M. (2006) Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444, 217–220
Yu, J. and Smith, G.P. (1996) Affinity maturation of phage-displayed peptide ligands. Meth. Enzymol. 267, 3–27
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This work was supported by the National Institutes of Health grants GM062134, GM069736, EB003968, and AI068730.
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Ricklin, D., Lambris, J. (2008). Compstatin: A Complement Inhibitor on its Way to Clinical Application. In: Lambris, J. (eds) Current Topics in Complement II. Advances in Experimental Medicine and Biology, vol 632. Springer, New York, NY. https://doi.org/10.1007/978-0-387-78952-1_20
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