Abstract
Activation of the complement system (Fig. 1) is the key to the development of normal inflammatory responses against foreign pathogens. During the course of this activation process a number of biological events are initiated, including generation of small peptides that induce local inflammatory responses, tagging of foreign pathogens with complement components that aid engulfment by phagocytes, and direct lysis of certain pathogens as a result of membrane attack complex (MAC) formation. Thus, complement deficiencies are often associated with a diminished ability to clear circulating immune complexes or to fight infection.
Chapter PDF
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Kalli, K. R., Hsu, P., and Fearon, D. T. (1994) Therapeutic uses of recombinant complement protein inhibitors. Springer Semin. Immunopathol. 15, 417–431.
Robbins, R. A., Russ, W. D., Rasmussen, J. K., and Clayton, M. M. (1987) Activation of the complement system in the adult respiratory distress syndrome. Am. Rev. Respir. Dis. 135, 651–658.
Bradt, B. M., Kolb, W. P., and Cooper, N. R. (1998) Complement-dependent proinflammatory properties of the Alzheimer’s disease beta-peptide. J. Exp. Med. 188, 431–438.
Rogers, J., Cooper, N. R., Webster, S., Schultz, J., Mcgeer, P. L., Styren, S. D., Civin, W. H., Brachova, L., Bradt, B., Ward, P., and Lieberburg, I. (1992) Complement activation by beta-amyloid in Alzheimer-disease. Proc. Natl. Acad. Sci. USA 89, 10016–10020.
Vasthare, U. S., Rosenwasser, R. H., Barone, F. C., and Tuma, R. F. (1993) Involvement of the complement system in cerebral ischemic and reperfusion injury. FASEB J. 7, A424.
Kilgore, K. S., Friedrichs, G. S., Homeister, J. W., and Lucchesi, B. R. (1994) The complement system in myocardial ischaemia/reperfusion injury. Cardiovasc. Res. 28, 437–444.
Gallinaro, R., Cheadle, W. G., Applegate, K., and Polk, H. C., Jr. (1992) The role of the complement system in trauma and infection. Surg. Gynecol. Obstet. 174, 435–440.
Beranek, J. T. (1997) Terminal complement-complex in myocardial reperfusion injury. Cardiovasc. Res. 33, 495–496.
Weiser, M. R., Williams, J. P., Moore, F. D., Kobzik, L., Ma, M. H., Hechtman, H. B., and Carroll, M. C. (1996) Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J. Exp. Med. 183, 2343–2348.
Johnson, R. J. (1991) Complement activation by biomaterials. Prog. Clin. Biol. Res. 337, 507–512.
Pekna, M., Nilsson, L., Nilsson Ekdahl, K., Nilsson, U. R., and Nilsson, B. (1993) Evidence for iC3 generation during cardiopulmonary bypass as the result of blood-gas interaction. Clin. Exp. Immunol. 91, 404–409.
Baldwin, W. M., Pruitt, S. K., Brauer, R. B., Daha, M. R., and Sanfilippo, F. (1995) Complement in organ-transplantation-contributions to inflammation, injury, and rejection. Transplantation 59, 797–808.
Dalmasso, A. P. (1992) The complement-system in xenotransplantation. Immunopharmacology 24 , 149–160.
Persidis, A. (1998) Complement inhibitors. Nature Biotech. 16, 882–883.
Lambris, J. D., Sahu, A., and Wetsel, R. (1998) The chemistry and biology of C3, C4, and C5, in The Human Complement System in Health and Disease (Volanakis, J. E. and Frank, M., eds.), Marcel Dekker, New York, pp. 83–118.
De Bruijn, M. H. L. and Fey, G. H. (1985) Human complement component C3: cDNA coding sequence and derived primary structure. Proc. Natl. Acad. Sci. USA 82, 708–712.
Huber, R., Scholze, H., Paques, E. P., and Deisenhofer, J. (1980) Crystal structure analysis and molecular model of human C3a anaphylatoxin. Hoppe Seylers Z. Physiol. Chemie. 361, 1389–1399.
Dolmer, K. and Sottrupjensen, L. (1993) Disulfide bridges in human complement component C3b. FEBS Lett. 315, 85–90.
Nagar, B., Jones, R. G., Diefenbach, R. J., Isenman, D. E., and Rini, J. M. (1998) X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Science 280, 1277–1281.
Hase, S., Kikuchi, N., Ikenaka, T., and Inoue, K. (1985) Structures of sugar chains of the third component of human complement. J. Biochem. (Tokyo) 98, 863–874.
Hirani, S., Lambris, J. D., and Muller-Eberhard, H. J. (1986) Structural analysis of the asparagine-linked oligosaccharides of human complement component C3. Biochem. J. 233, 613–616.
Müller-Eberhard, H. J., Dalmasso, A. P., and Calcott, M. A. (1966) The reaction mechanism of βlc-Globulin (C’3) in immune hemolysis. J. Exp. Med. 123, 33–54.
Law, S. K. A. and Dodds, A. W. (1997) The internal thioester and the covalent binding properties of the complement proteins C3 and C4. Prot. Sci. 6, 263–274.
Tack, B. F., Harrison, R. A., Janatova, J., Thomas, M. L., and Prahl, J. W. (1980) Evidence for presence of an internal thiolester bond in third component of human complement. Proc. Natl. Acad. Sci. USA 77, 5764–5768.
Sahu, A., Kozel, T. R., and Pangburn, M. K. (1994) Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation. Biochem. J 302, 429–436.
Sahu, A. and Pangburn, M. K. (1994) Covalent attachment of human complement C3 to IgG: Identification of the amino acid residue involved in ester linkage formation. J. Biol. Chem. 269, 28,997–29,002.
Kim, Y. U., Carroll, M. C., Isenman, D. E., Nonaka, M., Pramoonjago, P., Takeda, J., Inoue, K., and Kinoshita, T. (1992) Covalent binding of C3b to C4b within the classical complement pathway C5 convertase: determination of amino acid residues involved in ester linkage formation. J. Biol. Chem. 267, 4171–4176.
Kinoshita, T., Takata, Y., Kozono, H., Takeda, J., Hong, K., and Inoue, K. (1988) C5 convertase of the alternative complement pathway: covalent linkage between two C3b molecules within the trimolecular complex enzyme. J. Immunol. 141, 3895–3901.
Gigli, I., von Zabern, I., and Porter, R. R. (1977) The isolation and structure of C4, the fourth component of human complement. Biochem. J. 165, 439–446.
Schreiber, R. D. and Muller-Eberhard, H. J. (1974) Fourth component of human complement: Description of a three chain structure. J. Exp. Med. 140, 1324–1335.
Seya, T., Nagasawa, S., and Atkinson, J. P. (1986) Location of the interchain disulfide bonds of the fourth component of human complement (C4): evidence based on the liberation of fragments secondary to thiol-disulfide interchange reactions. J. Immunol. 136, 4152–4156.
Belt, K. T., Carroll, M. C., and Porter, R. R. (1984) The structural basis of the multiple forms of human complement component C4. Cell 36, 907–914.
Chan, A. C. and Atkinson, J. P. (1985) Oligosaccharide structure of human C4. J. Immunol. 134, 1790–1798.
Goldberger, G. and Colten, H. R. (1980) Precursor complement protein (pro-C4) is converted in vitro to native C4 by plasmin. Nature 286, 514–516.
Karp, D. R. (1983) Post-translational modification of the fourth component of complement. Sulfation of the alpha chain. J. Biol. Chem. 258, 12,745–12,748.
Chan, A. C., Mitchell, K. R., Munns, T. W., Karp, D. R., and Atkinson, J. P. (1983) Identification and partial characterization of the secreted form of the fourth component of human complement. Evidence that it is different from major plasma form. Proc. Natl. Acad. Sci. USA 80, 268–272.
Pangburn, M. K. (1992) Spontaneous thioester bond formation in alpha 2-macroglobulin, C3 and C4. FEBS Lett. 308, 280–282.
Matsushita, M. and Fujita, T. (1992) Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J. Exp. Med. 176, 1497–1502.
Isenman, D. E. and Young, J. R. (1984) The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J. Immunol. 132, 3019–3027.
Law, S. K. A., Dodds, A. W., and Porter, R. R. (1984) A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J. 3, 1819–1823.
Bolotin, C., Morris, S., Tack, B., and Prahl, J. (1977) Purification and structural analysis of the fourth component of human complement. Biochemistry 16, 2008–2015.
Matsushita, M., Takahashi, M., Thiel, S., Jensenius, J. C., and Fujita, T. (1998) Distinct proteolytic activities of MASP-1 and MASP-2. Mol. Immunol. 35, 349.
Kerr, M. A. (1980) The human complement system: assembly of the classical pathway C3 convertase. Biochem. J. 189, 173–181.
Muller-Eberhard, H. J., Polley, M. J., and Calcott, R. M. (1967) Formation and functional significance of a molecular complex derived from the second and the fourth component of human complement. J. Exp. Med. 125, 359–380.
Press, E. M. and Gagnon, J. (1981) Human complement component C4: structural studies on the fragments derived from C4b by cleavage with C3b inactivator. Biochem. J. 199, 351–357.
von Zabern, I., Bloom, E. L., Chu, V., and Gigli, I. (1982) The fourth component of human complement treated with amines or chaotropes or frozen-thawed (C4b-Like C4): interaction with C4 binding protein and cleavage by C3b/C4b inactivator. J. Immunol. 128, 1433–1438.
Kinoshita, T., Medof, M. E., Hong, K., and Nussenzweig, V. (1986) Membrane-bound C4b interacts endogenously with complement receptor CR 1 of human red cells. J. Exp. Med. 164, 1377–1388.
Seya, T., Turner, J. R., and Atkinson, J. P. (1986) Purification and characterization of a membrane protein (gp45–70) that is a cofactor for cleavage of C3b and C4b. J. Exp. Med. 163, 837–855.
Tomana, M., Niemann, M., Garner, C., and Volanakis, J. E. (1985) Carbohydrate composition of the second, third and fifth components and factors B and D of human complement. Mol. Immunol. 22, 107–111.
DiScipio, R. G., Smith, C. A., Müller-Eberhard, H. J., and Hugli, T. E. (1983) The activation of human complement component C5 by a fluid phase C5 convertase. J. Biol. Chem. 258, 10,629–10,636.
Ooi, Y. M. and Colten, H. R. (1979) Biosynthesis and post-synthetic modification of a precursor (pro-05) of the fifth component of mouse complement (C5). J. Immunol. 123, 2494–2498.
Ooi, Y. M., Harris, D. E., Edelson, P. J., and Cotten, H. R. (1980) Posttranslational control of complement (C5) production by resident and stimulated mouse macrophages. J. Immunol. 124, 2077–2081.
DiScipio, R. G. and Stura, E. A. (1996) Crystallization of human complement component C5. Mol. Immunol. 33, 43–43 (Abstr).
Perkins, S. J., Smith, K. F., Nealis, A. S., Lachmann, P. J., and Harrison, R. A. (1990) Structural homologies of component C5 of human complement with components C3 and C4 by neutron scattering. Biochemistry 29, 1175–1180.
Goetzl, E. J. and Austen, K. F. (1974) Stimulation of neutrophil leucocyte aerobic glucose metabolism by purified chemotactic factors. J. Clin. Invest. 53, 591–599.
Gerard, C. and Hugli, T. E. (1981) Identification of classical anaphylatoxin as the des-Arg form of the C5a molecule: evidence of a modulator role for the oligosaccharide unit in human des-Arg74–05a. Proc. Natl. Acad. Sci. USA 78, 1833–1837.
Chenoweth, D. E. and Hugli, T. E. (1980) Human C5a and C5a analogs as probes for the neutrophil C5a receptor. Mol. Immunol. 17, 151–161.
Webster, R. O., Hong, S. R., Johnston, R. B., Jr., and Henson, P. M. (1980) Biological effects of the human complement fragments C5a and C5ades Arg on neutrophil function. Immunopharmacology 2, 201–219.
Weisman, H. F., Bartow, T., Leppo, M. K., Marsh, H. C. Jr., Carson, G. R., Concino, M. F., Boyle, M. P., Roux, K. H., Weisfeldt, M. L., and Fearon, D. T. (1990) Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249, 146–151.
Lachmann, P. J. and Davies, A. (1997) Complement and immunity to viruses. Immunol. Rev. 159, 69–77.
Cooper, N. R. (1991) Complement evasion strategies of microorganisms. Immunol. Today 12, 327–331.
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.
Kotwal, G. J., and Moss, B. (1988) Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins. Nature 335, 176–178.
Kotwal, G. J., Isaacs, S. N., Mckenzie, R., Frank, M. M., and Moss, B. (1990) Inhibition of the complement cascade by the major secretory protein of vaccinia virus. Science 250, 827–830.
Isaacs, S. N., Kotwal, G. J., and Moss, B. (1992) Vaccinia virus complement-control protein prevents antibody-dependent complement-enhanced neutralization of infectivity and contributes to virulence. Proc. Natl. Acad. Sci. USA 89, 628–632.
Mckenzie, R., Kotwal, G. J., Moss, B., Hammer, C. H., and Frank, M. M. (1992) Regulation of complement activity by vaccinia virus complementcontrol protein. J. Infect. Dis. 166, 1245–1250.
Sahu, A., Isaacs, S. N., Soulika, A. M., and Lambris, J. D. (1998) Interaction of vaccinia virus complement control protein with human complement proteins: factor I-mediated degradation of C3b to iC3b1 inactivates the alternative complement pathway. J. Immunol. 160, 5596–5604.
Massung, R. F., Esposito, J. J., Liu, L. I., Qi, J., Utterback, T. R., Knight, J. C., Aubin, L., Yuran, T. E., Parsons, J. M., Loparev, V. N., Selivanov, N. A., Cavallaro, K. F., Kerlavage, A. R., Mahy, B. W. J., and Venter, J. C. (1993) Potential virulence determinants in terminal regions of variola smallpox virus genome. Nature 366, 748–751.
Shchelkunov, S. N., Blinov, V. M., Totmenin, A. V., Marennikova, S. S., Kolykhalov, A. A., Frolov, I. V., Chizhikov, V. E., Gutorov, V. V., Gashnikov, P. V., Belanov, E. F., Belavin, P. A., Resenchuk, S. M., Shelikhina, E. M., Netesov, S. V., Andzhaparidze, O. G., and Sandakhchiev, L. S. (1992) Structural-functional organization of the smallpox virus genome. 1. cloning of viral-DNA HINDIII and XHOI fragments and sequencing of HINDIII fragment-M, fragment-L, and fragment-I. Mol. Biol. 26, 731–744.
Albrecht, J. C. and Fleckenstein, B. (1992) New member of the multigene family of complement control proteins in herpesvirus saimiri. J. Virol. 66, 3937–3940.
Fodor, W. L., Rollins, S. A., Biancocaron, S., Rother, R. P., Guilmette, E. R., Burton, W. V., Albrecht, J. C., Fleckenstein, B., and Squinto, S. P. (1995) The complement control protein homolog of herpesvirus saimiri regulates serum complement by inhibiting C3 convertase activity. J. Virol. 69, 3889–3892.
Russo, J. J., Bohenzky, R. A., Chien, M. C., Chen, J., Yan, M., Maddalena, D., Parry, J. P., Peruzzi, D., Edelman, I. S., Chang, Y. A., and Moore, P. S. (1996) Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc. Natl. Acad. Sci. USA 93, 14,862–14,867.
Virgin, H. W., Latreille, P., Wamsley, P., Hallsworth, K., Weck, K. E., DalCanto, A. J., and Speck, S. H. (1997) Complete sequence and genomic analysis of murine gammaherpesvirus 68. J. Virol. 71, 5894–5904.
Bruggemann, M. and Taussig, M. J. (1997) Production of human antibody repertoires in transgenic mice. Curr. Opin. Biotechnol. 8, 455–458.
Fishwild, D. M., ODonnell, S. L., Bengoechea, T., Hudson, D. V., Harding, F., Bernhard, S. L., Jones, D., Kay, R. M., Higgins, K. M., Schramm, S. R., and Lonberg, N. (1996) High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat. Biotech. 14, 845–851.
Wang, X., Sahu, A., Pangburn, M. K., and Wetsel, R. A. (1996) Inhibition of C5 cleavage but not C5 binding by a monoclonal antibody that recognizes an 85 aamino acid region of C5 3-chain. Mol. Immunol. 33, 56 (Abstr).
Wurzner, R., Schulze, M., Happe, L., Franzke, A., Bieber, F. A., Oppermann, M., and Gotze, O. (1991) Inhibition of terminal complement complexformation and cell-lysis by monoclonal-antibodies. Compl. Inflam. 8, 328–340.
Rollins, S. A., Fitch, J. C. K., Shernan, S., Rinder, C. S., Rinder, H. M., Smith, B. R., Collard, C. D., Stahl, G. L., Alford, B. L., Li, L., and Matis, L. A. (1998) Anti-CS single chain antibody therapy blocks complement and leukocyte activation and reduces myocardial tissue damage in CPB patients. Mol. Immunol. 35, 397.
Rinder, C. S., Rinder, H. M., Smith, B. R., Fitch, J. C. K., Smith, M. J., Tracey, J. B., Matis, L. A., Squinto, S. P., and Rollins, S. A. (1995) Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal-circulation. J. Clin. Invest. 96, 1564–1572.
Wang, Y., Hu, Q. L., Madri, J. A., Rollins, S. A., Chodera, A., and Matis, L. A. (1996) Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5 Proc. Natl. Acad. Sci. USA 93, 8563–8568.
Wang, Y., Rollins, S. A., Madri, J. A., and Matis, L. A. (1995) Anti-CS monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc. Natl. Acad. Sci. USA 92, 8955–8959.
Vakeva, A. P., Agah, A., Rollins, S. A., Matis, L. A., Li, L., and Stahl, G. L. (1998) Myocardial infarction and apoptosis after myocardial ischemia and reperfusion—Role of the terminal complement components and inhibition by anti-05 therapy. Circulation 97, 2259–2267.
Evans, M. J., Rollins, S. A., Wolff, D. W., Rother, R. P., Norin, A. J., Therrien, D. M., Grijalva, G. A., Mueller, J. P., Nye, S. H., Squinto, S. P., and Wilkins, J. A. (1995) In vitro and in vivo inhibition of complement activity by a single-chain Fv fragment recognizing human C5. Mol. Immunol. 32, 1183–1195.
Sahu, A., Saha, K., Kashyap, A., and Chakrabarty, A. K. (1988) Interaction of anti-leprosy drugs with the rat serum complement system. Immunopharmacol. 15, 143–150.
Reynard, A. M. (1980) The regulation of complement activity by pharmacologic agents. J. Immunopharmacology 2, 1–47.
Johnson, B. J. (1977) Complement: a host defense mechanism ready for pharmacological manipulation? J. Pharmaceut. Sci. 66, 1367–1377.
Makrides, S. C. (1998) Therapeutic inhibition of the complement system. Pharmacol. Rev. 50, 59–87.
Asghar, S. S. (1984) Pharmacological manipulation of complement system. Pharmacol. Rev. 36, 223–244.
Meri, S. and Pangburn, M. K. (1990) A mechanism of activation of the alternative complement pathway by the classical pathway protection of C3b from inactivation by covalent attachment to C4b. Eur. J. Immunol. 20, 2555–2561.
Reid, K. B. M. and Turner, M. W. (1994) Mammalian lectins in activation and clearance mechanisms involving the complement system. Springer Semin. Immunopathol. 15, 307–326.
Matsushita, M. (1996) The lectin pathway of the complement system. Microbiol. Immunol. 40, 887–893.
Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., and Steele, J. (1995) Combinatorial synthesis the design of compound libraries and their application to drug discovery. Tetrahedron 51, 8135–8173.
Kay, B. K., Kurakin, A. V., and Hyde-DeRuyscher, R. (1998) From peptides to drugs via phage display. Drug Discovery Today 3, 370–378.
Scott, J. K. and Smith, G. P. (1990) Searching for peptide ligands with an epitope library. Science 249, 386–390.
Sparks, A. B., Quilliam, L. A., Thorn, J. M., Der, C. J., and Kay, B. K. (1994) Identification and characterization of Src SH3 ligands from phage-displayed random peptide libraries. J. Biol. Chem. 269, 23,853–23,856.
Blond-Elguindi, S., Cwirla, S. E., Dower, W. J., Lipshutz, R. J., Sprang, S. R., Sambrook, J. F., and Gething, M.-J. H. (1993) Affinity panning of a library of peptides dispalyed on bacteriophages reveals the binding specificity of BiP. Cell 75, 717–728.
Dedman, J. R., Kaetzel, M. A., Chan, H. C., Nelson, D. J., and Jamieson, G. A., Jr. (1993) Selection of targeted biological modifiers fron a bacteriophage library of random peptides: The identification of novel calmodulin regulatory peptides. J Biol. Chem. 268, 23,025–23,030.
Devlin, J. J., Panganiban, L. C., and Devlin, P. E. (1990) Random peptide libraries: a source of specific protein binding molecules. Science 245, 404–406.
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. and Pangburn, M. K. (1996) Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3. Biochem. Pharmacol. 51, 797–804.
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.
Klepeis, J. L., Floudas, C. A., Morikis, D., and Lambris, J. D. (1999) Predicting peptide structures using NMR data and deterministic global optimization. J. Comput. Chem. 20, 1354–1370.
Wilmot, C. M. and Thornton, J. M. (1988) Analysis and prediction of the different types of beta-turn in proteins. J. Mol. Biol. 203, 221–232.
Sahu, A., Morikis, D., Soulika, A. M., Spruce, L., Moore, W. T., and Lambris, J. D. (1998) Species specificity, structural functional analysis and biotransformation studies on Compstatin, a potent complement inhibitor. Mol. Immunol. 35, 371–371.
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. (1999) Prolongation of ex-vivo-perfused pig xenograft survival by the complement inhibitor Compstatin. Transplant. Proc. 31, 934–935.
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. (1999) Prolongation of ex-vivo-perfused pig xenograft survival by the complement inhibitor Compstatin. Transplant. Proc. 31, 934–935.
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.
Levine, R. P. and Dodds, A. W. (1990) The thiolester bond of C3. Curr. Top. Microbiol. Immunol. 153, 73–82.
Law, S. K., Lichtenberg, N. A., and Levine, R. P. (1980) Covalent binding and hemolytic activity of complement proteins. Proc. Natl. Acad. Sci. USA 77, 7194–7198.
Law, S. A., Minich, T. M., and Levine, R. P. (1981) Binding reaction between the third human complement protein and small molecules. Biochemistry 20, 7457–7463.
Gordon, J., Whitehead, H., and Wormall, A. (1926) The action of ammonia on complement. The fourth component. Biochem. J. 20, 1028–1035.
Pangburn, M. K. and Müller-Eberhard, H. J. (1980) Relation of a putative thioester bond in C3 to activation of the alternative pathway and the binding of C3b to biological targets of complement. J. Exp. Med. 152, 1102–1114.
Sahu, A. and Pangburn, M. K. (1995) Tyrosine is a potential site for covalent attachment of activated commplement component C3. Mol. Immunol. 32, 711–716.
Biesecker, G., Dihel, L., Enney, K., and Bendele, R. (1998) Derivation of RNA aptamer inhibitors of human C5. Mol. Immunol. 35, 334.
Ecker, E. E. and Gross, P. (1929) Anticomplementary power of heparin. J. Infect. Dis. 44, 250–253.
Wan, S., LeClerc, J. L., and Vincent, J. L. (1997) Inflammatory response to cardiopulmonary bypass mechanisms involved and possible therapeutic strategies. Chest 112, 676–692.
Marsters, S. A., Ayres, T. M., Skubatch, M., Gray, C. L., Rothe, M., and Ashkenazi, A. (1997) Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kappa B and AP-1. J. Biol. Chem. 272, 14,029–14,032.
Raepple E., Hill H. U., and Loos M. (1976) Mode of interaction of different polyanions with the first (C1), the second (C2) and the fourth (C4) component of complement I. effect on fluid phase C1 and on C1 bound to EA or to EAC4. Immunochemistry 13, 251–255.
Weiler J. M., Yurt R. W., Fearon D. T., and Austen, K. F. (1978) Modulation of the formation of the amplification convertase of complement, C3b, Bb, by native and commercial heparin. J. Exp. Med. 147, 409–421.
Weiler, J. M. and Linhardt, R. J. (1989) Comparison of the activity of polyanion and polycations on the classical and alternative pathways of complement. Immunopharmacology 17, 65–72.
Weiler, J. M., Edens, R. E., Linhardt, R. J., and Kapelanski, D. P. (1992) Heparin and modified heparin inhibit complement activation in vivo. J. Immunol. 148, 3210–3215.
Sahu, A. and Pangburn, M. K. (1993) Identification of multiple sites of interaction between heparin and the complement system. Mol. Immunol. 30, 679–684.
Loos, M., Volanakis, J. E., and Stroud, R. M. (1976) Mode of interaction of different polyanions with the first (C1), the second (C2) and the fourth (C4) component of complement II: effect of polyanions on the binding of C2 to EAC4b. Immunochemistry 13, 257–261.
Loos, M., Volanakis, J. E., and Stroud, R. M. (1976) Mode of interaction of different polyanions with the first (C1), the second (C2) and the fourth (C4) component of complement III: inhibition of C4 and C2 binding site(s) on C1s by polyanions. Immunochemistry 13, 789–791.
Fosse, E., Moen, O., Johnson, E., Semb, G., Brockmeier, V., Mollnes, T. E., Fagerhol, M. K., and Venge, P. (1994) Reduced complement and granulocyte activation with heparin- coated cardiopulmonary bypass. Ann. Thorac. Surg. 58, 472–477.
Svennevig, J. L., Geiran, O. R., Karlsen, H., Pedersen, T., Mollnes, T. E., Kongsgard, U., and Froysaker, T. (1993) Complement activation during extracorporeal circulation in vitro comparison of Duraflo-II heparin-coated and uncoated oxygenator circuits. J. Thorac. Cardiovasc. Surg. 106, 466–472.
Nilsson, U. R., Larm, O., Nilsson, B., Storm, K. E., Elwing, H., and Ekdahl, K. N. (1993) Modification of the complement binding properties of polystyrene—effects of end-point heparin attachment. Scand. J. Immunol. 37, 349–354.
Pekna, M., Hagman, L., Halden, E., Nilsson, U. R., Nilsson, B., and Thelin, S. (1994) Complement activation during cardiopulmonary bypass: effects of immobilized heparin. Ann. Thorac. Surg. 58, 421–424
Kazatchkine, M. D., Fearon, D. T., Metcalfe, D. D., Rosenberg, R. D., and Austen, K. F. (1981) Structural determinants of the capacity of heparin to inhibit the formation of the amplification C3 convertase. J. Clin. Invest. 67, 223–228.
Englberger, W., Hadding, U., Etschenberg, E., Graf, E., Leyck, S., Winkelmann, J., and Parnham, M. J. (1988) Rosmarinic acid- a new inhibitor of complement C3 convertase with anti-inflammatory activity. Int. J. Immunopharmacol. 10, 729–737.
Sahu, A., Rawal, N., and Pangburn, M. K. (1999) Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b. Biochem. Pharmacol. 57, 1439–1446.
Leyck, E., Etschenberg, E., Hadding, U., and Winkelmann, J. (1983) A new model of acute inflammation: cobra venom factor induced paw oedema. Agents Actions 13, 437–438.
Rampart, M., Beetens, J. R., Bult, H., Herman, A. G., Parnham, M. J., and Winkelmann, J. (1986) Complement-dependent stimulation of prostacyclin biosynthesis: inhibition by rosmarinic acid. Biochem. Pharmacol. 35, 1397–1400.
Peake, P. W., Pussell, B. A., Martyn, P., Timmermans, V., and Charlesworth, J. A. (1991) The inhibitory effect of rosmarinic acid on complement involves the C5 convertase. Int. J. Immunopharmacol. 13, 853–857.
Miyazaki, W., Tomaoka, H., Shinohara, M., Kaise, H., Izawa, T., Nakano, Y., Kinoshita, T., Hong, K., and Inoue, K. (1980) A complement inhibitor produced by Stachybotrys complementi, nov. sp. K-76, a new species of fungi imperfecti. Microbiol. Immunol. 24, 1091–1108.
Hong, K., Kinoshita, T., Miyazaki, W., Izawa, T., and Inoue, K. (1979) An anticomplementary agent, K-76 monocarboxylic acid: its site and mechanism of inhibition of the complement activation cascade. J. Immunol. 122, 2418–1223.
Hong, K., Kinoshita, T., Kitajima, H., and Inoue, K. (1980) Inhibitory effect of K-76 monocarboxylic acid, an anticomplementary agent, on the C3b inactivator system. J. Immunol. 127, 104–108.
Konno, S. and Tsurufuji, S. (1983) Induction of zymosan-air-pouch inflammation in rats and its characterization with reference to the effects of anticomplementary and anti-inflammatory agents. Br. J. Pharmacol. 80, 269–277.
Iida, H., Izumino, K., Asaka, M., Takata, M., Mizumura, Y., and Sasayama, S. (1987) Effect of anticomplementary agent, K-76 monocarboxylic acid, on experimental immune complex glomerulonephritis in rats. Clin. Expt. Immunol. 67, 130–134.
Yamada, H., Kudoh, I., Nishizawa, H., Kaneko, K., Miyazaki, H., Ohara, M., and Okumura, F. (1997) Complement partially mediates acid aspiration-induced remote organ injury in the rat. Acta Anaesthesiol. Scand. 41, 713–718
Tanaka, M., Murase, N., Ye, Q., Miyazaki, W., Nomoto, M., Miyazawa, H., Manez, R., Toyama, Y., Demetris, A. J., Todo, S., and Starzl, T. E. (1996) Effect of anticomplement agent K76 COOH on hamster-to-rat and guinea pig-to-rat heart xenotransplantation. Transplantation 62, 681–688.
Blum, M. G., Collins, B. J., Chang, A. C., Zhang, J. P., Knaus, S. A., and Pierson, R. N. (1998) Complement inhibition by FUT-175 and K76-COOH in a pig-to-human lung xenotransplant model. Xenotransplantation 5, 35–43.
Kobayashi, T., Neethling, F. A., Taniguchi, S., Ye, Y., Niekrasz, M., Koren, E., Hancock, W. W., Takagi, H., and Cooper, D. K. C. (1996) Investigation of the anti-complement agents, FUT-175 and K76COOH, in discordant xenotransplantation. Xenotransplantation 3, 237–245.
Grindley, J. N. and Ogden, J. E. (1995) Forecasting the future for protein drugs. Scrip. Mag. November, 53–56.
Ahearn, J. M. and Fearon D. T. (1989) Structure and function of the complement receptors, CR1 (CD35), and CR2 (CD21). Adv. Immunol. 46, 183–219.
Dellinger, R. P., Zimmerman, J. L., Straube, R. C., Metzler, M. H., Wall, M., Brown, B. K., Levin, J. L., Toth, C. A., and Ryan, U. S. (1996) Results of phase I trial of soluble complement receptor type 1 (TP10) in acute lung injury (ALI). Crit. Care Med. 24 (Suppl. 2), A29.
Ryan, U. S. (1995) Complement inhibitory therapeutics and xenotransplantation. Nat . Med. 1, 967–968.
Medof, M. E., Kinoshita, T., and Nussenzweig,V. (1984) Inhibition of complement activation on the surface of cells after incorporation of decay-acceleration factor (DAF) into their membranes. J. Exp. Med. 160, 1558–1578.
Fujita, T., Inoue, T., Ogawa, K., Iida, K., and Tamura, N. (1987) The mechanism of action of decay-accelerating factor (DAF): DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb. J. Exp. Med. 166, 1221–1228.
Christiansen, D., Milland, J., Thorley, B. R., Mckenzie, I. F. C., and Loveland, B. E. (1996) A functional analysis of recombinant soluble CD46 in vivo and a comparison with recombinant soluble forms of CD55 and CD35 in vitro. Eur. J. Immunol. 26, 578–585.
Oglesby, T. J., Allen, C. J., Liszewski, M. K., White, D. J. G., and Atkinson, J. P. (1992) Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism. J. Exp. Med. 175,1547–1551
Whaley, K., and Ruddy, S. (1976) Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193, 1011–1013.
Weiler J. M., Daha, M. R., Austen, K. F., and Fearon D. T. (1976) Control of the amplification convertase of complement by the plasma protein beta 1 H. Proc. Natl. Acad. Sci. USA 73, 3268–3272.
Pangburn, M. K., Schreiber, R. D., and Müller-Eberhard, H. J. (1977) Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein 131H for cleavage of C3b and C4b in solution. J. Exp. Med. 146, 257–270.
Goldberger, G., Bruns, G. A., Rits, M., Edge, M. D., and Kwiatkowski, D. J. (1987) Huamn complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4. J. Biol. Chem. 262,10,065–10,071.
Chamberlain, D., Ullman, C. G., and Perkins, S. J. (1998) Possible arrangement of the five domains in human complement factor I as determined by a combination of X-ray and neutron scattering and homology modeling. Biochemistry 37, 13918–13929.
Chung, L. P., Bentley, D. R., and Reid, K. B. M. (1985) Molecular cloning and characterization of the cDNA coding for C4b-binding protein, a regulatory protein of theclassical pathway of the human complement system. Biochem. J. 230, 133–141.
Gigli, I., Fujita, T., and Nussenzweig, V. (1979) Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc. Natl. Acad. Sci. USA 76, 6596–6600.
Lopez Trascasa, M., Bing, D. H., Rivard, M., and Nicholson-Weller, A. (1989) Factor Jisolation and characterization of a new polypeptide inhibitor of complement C1. J. Biol. Chem. 264, 16,214–16,221.
Gonzalez Rubio, C., Jimenez Clavero, M. A., Fontan, G., and Lopez Trascasa, M. (1994) The inhibitory effect of factor J on the alternative complement pathway. J. Biol. Chem. 269, 26,017–26,024.
Jimenezclavero, M. A., Gonzalezrubio, C., Larrucea, S., Gamallo, C., Fontan, G., and Lopeztrascasa, M. (1995) Cell-surface molecules related to factor J in human lymphoid cells and cell-lines. J. Immunol. 155, 2143–2150.
Giclas, P. C., King, T. E., Baker, S. L., Russo, J., and Henson, P. M. (1987) Complement activity in normal rabbit bronchoalveolar fluid description of an inhibitor of C3 activation. Am. Rev. Respir. Dis. 135, 403–411.
Iwata, K., Seya, T., Ariga, H., and Nagasawa, S. (1994) Expression of a hybrid complement regulatory protein, membrane cofactor protein-decay accelerating factor on chinese hamster ovary Comparison of its regulatory effect with those of decay accelerating factor and membrane cofactor protein. J. Immunol. 152, 3436–3444.
Higgins, P. J., Ko, J. L., Lobell, R., Sardonini, C., Alessi, M. K., and Yeh, C. G. (1997) A soluble chimeric complement inhibitory protein that possesses both decay-accelerating and factor I cofactor activities. J. Immunol. 158, 2872–2881.
Fodor, W. L., Rollins, S. A., Guilmette, E. R., Setter, E., and Squinto, S. P. (1995) A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex. J. Immunol. 155, 4135–4138.
Miller, C. G., Shchelkunov, S. N., and Kotwal, G. J. (1997) The cowpox virus-encoded homolog of the vaccinia virus complement control protein is an inflammation modulatory protein. Virology 229, 126–133.
Rosengard, A. M. and Ahearn, J. M. (1998) Creation and functional characterization of spice, the small pox inhibitor of complement enzymes. Mol. Immunol. 35, 397.
Kretzschmar, T., Pohl, M., Casaretto, M., Przewosny, M., Bautsch, W., Klos, A., Saunders, D., and Kohl, J. (1992) Synthetic peptides as antagonists of the anaphylotoxin C3a. Eur. J. Biochem. 210, 185–191.
Kossorotow, A., Optiz, W., Etschenberg, E., and Hadding, U. (1977) Studies on C3 convertase: inhibition of C5 convertase formation by peptides containing aromatic amino acids. Biochem. J. 167, 377–382.
Pellas, T. C., Boyar, W., van Oostrum, J., Wasvary, J., Fryer, L. R., Pastor, G., Sills, M., Braunwalder, A., Yarwood, D. R., Kramer, R., Kimble, E., Hadala, J., Haston, W., Moreira-Ludewig, R., Uziel-Fusi, S., Peters, P., Bill, K., and Wennogle, L. P. (1998) Novel C5a receptor antagonists regulate neutrophil functions in vitro and in vivo. J. Immunol. 160, 5616–5621.
Zhang, X. L., Boyar, W., Galakatos, N., and Gonnella, N. C. (1997) Solution structure of a unique C5a semi-synthetic antagonist: Implications in receptor binding. Prot. Sci. 6, 65–72.
Konteatis, Z. D., Siciliano, S. J., Vanriper, G., Molineaux, C. J., Pandya, S., Fischer, P., Rosen, H., Mumford, R. A., and Springer, M. S. (1994) Development of C5a receptor antagonists differential loss of functional responses. J. Immunol. 153, 4200–4205.
Baranyi, L., Campbell, W., and Okada, H. (1996) Antisense homology boxes in C5a receptor and C5a anaphylatoxin—a new method for identification of potentially active peptides. J. Immunol. 157, 4591–4601.
Kaufman, T. S., Srivastava, R. P., Sindelar, R. D., Scesney, S. M., and Marsh, H. C. (1995) Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors. J. Med. Chem. 38, 1437–1445.
Kaufman, T. S., Srivastava, R. P. S., Sindelar, R. D., Scesney, S. M., and Marsh, H. C. (1995) Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors —a potential probe for the absolute stereochemistry at position. Bioorg. Med. Chem. Lett. 5, 501–506.
Sindelar, R. D., Srivastava, R. P., Bartyzel, P., Assefa, H., Walker, L. A., Zhu, X., Marsh, H. C., and Scesney, S. M. (1997) The design, synthesis and evaluation of potential human complement inhibitors based on a natural product model. Abstr. Am. Chem. Soc. 214(Pt 1), U93–U93.
Fujii, S. and Hitomi, Y. (1981) New synthetic inhibitors of C1 r, C1 esterase, thrombin, plasmin, kallikren and trypsin. Biochim. Biophys. Acta 661, 342–345.
Ikari, N., Sakai, Y., Hitomi, Y., and Fujii, S. (1983) New synthetic inhibitor to the alternative complement pathway. Immunology 49, 685–691.
Homeister, J. W., Satoh, P., and Lucchesi, B. R. (1992) Effects of complement activation in the isolated heart role of the terminal complement components. Circ. Res. 71, 303–319.
Inose, K., Ono, K., Tsutida, A., Onai, M., Komai, M., Uchara, K., Yano, S., and Naruse, T. (1997) Active inhibitory effect of nafamostat mesylate against the elevation of plasma myeloperoxidase during hemodialysis. Nephron 75, 420–425.
Blondin, C., Fischer, E., Boissonvidal, C., Kazatchkine, M. D., and Jozefonvicz, J. (1994) Inhibition of complement activation by natural sulfated polysaccharides (fucans) from brown seaweed. Mol. Immunol. 31, 247–253.
Charreau, B., Blondin, C., Boisson-Vidal, C., Soulillou, J. P., and Anegon, I. (1997) Efficiency of fucans in protecting porcine endothelial cells against complement activation and lysis by human serum. Transplant. Proc. 29, 889–890.
Quigg, R. J. (1992) Inhibition of the alternative pathway of complement by glomerular chondroitin sulphate proteoglycan. Immunology 76, 373–377
Georgieva, P., Ivanovska, N., Bankova, V., and Popov, S. (1997) Anticomplement activity of lysine complexes of propolis phenolic constituents and their synthetic analogs. Zeitsch. Naturforsch. C-A J. Biosci. 52, 60–64.
Jansen, J. A. (1969) A specific inactivator of mammalian C’4 isolated from nurse shark (Ginglymostroma cirratum) serum. J. Exp. Med. 130, 217–241.
Hensens, O. D., Borris, R. P., Koupal, L. R., Caldwell, C. G., Currie, S. A., Haidri, A. A., Homnick, C. F., Honeycutt, S. S., Lindnmayer, S. M., Schwartz, C. D., Weissberger, B. A., Woodruff, H. B., Zink, D. L., Zitano, L., Fieldhouse, J. M., Rollins, T., Springer, M. S., and Springer, J. P. (1991) L-156,602, a C5a antagonist with a novel cyclic hexadepsipeptide structure from streptomyces-Sp MA6348—fermentation, isolation and structure determination J. Antibiotics 44, 249–254.
Tsuji, R. F., Magae, J., Nagai, K., and Yamasaki, M. (1992) Effects of L-156,602, a C5a receptor antagonist, on experimental models of inflammation. Biosci. Biotechnol. Biochem. 56, 2034–2036.
Tsuji, R. F., Uramoto, M., Koshino, H., Tsuji, N. M., Magae, J., Nagai, K., and Yamasaki, M. (1992) Preferential suppression of delayed-type hypersensitivity by L-156,602, a C5a receptor antagonist. Biosci. Biotechnol. Biochem. 56, 1686–1689.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Sahu, A., Morikis, D., Lambris, J.D. (2000). Complement Inhibitors Targeting C3, C4, and C5. In: Lambris, J.D., Holers, V.M. (eds) Therapeutic Interventions in the Complement System. Contemporary Immunology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-017-9_4
Download citation
DOI: https://doi.org/10.1007/978-1-59259-017-9_4
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-4684-9612-3
Online ISBN: 978-1-59259-017-9
eBook Packages: Springer Book Archive