Complement Inhibitors Targeting C3, C4, and C5

  • Arvind Sahu
  • Dimitrios Morikis
  • John D. Lambris
Part of the Contemporary Immunology book series (CONTIM)


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.


Complement Component Rosmarinic Acid Membrane Attack Complex Human Complement Lectin Pathway 
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.


  1. 1.
    Kalli, K. R., Hsu, P., and Fearon, D. T. (1994) Therapeutic uses of recombinant complement protein inhibitors. Springer Semin. Immunopathol. 15, 417–431.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    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.Google Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedGoogle Scholar
  8. 8.
    Beranek, J. T. (1997) Terminal complement-complex in myocardial reperfusion injury. Cardiovasc. Res. 33, 495–496.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 10.
    Johnson, R. J. (1991) Complement activation by biomaterials. Prog. Clin. Biol. Res. 337, 507–512.Google Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedGoogle Scholar
  13. 13.
    Dalmasso, A. P. (1992) The complement-system in xenotransplantation. Immunopharmacology 24 , 149–160.PubMedCrossRefGoogle Scholar
  14. 14.
    Persidis, A. (1998) Complement inhibitors. Nature Biotech. 16, 882–883.CrossRefGoogle Scholar
  15. 15.
    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.Google Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    Dolmer, K. and Sottrupjensen, L. (1993) Disulfide bridges in human complement component C3b. FEBS Lett. 315, 85–90.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    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.Google Scholar
  21. 21.
    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.PubMedGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedGoogle Scholar
  26. 26.
    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.Google Scholar
  27. 27.
    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.PubMedGoogle Scholar
  28. 28.
    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.PubMedGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    Chan, A. C. and Atkinson, J. P. (1985) Oligosaccharide structure of human C4. J. Immunol. 134, 1790–1798.PubMedGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    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.Google Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Pangburn, M. K. (1992) Spontaneous thioester bond formation in alpha 2-macroglobulin, C3 and C4. FEBS Lett. 308, 280–282.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    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.CrossRefGoogle Scholar
  43. 43.
    Kerr, M. A. (1980) The human complement system: assembly of the classical pathway C3 convertase. Biochem. J. 189, 173–181.PubMedGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedGoogle Scholar
  46. 46.
    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.Google Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    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.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedCrossRefGoogle Scholar
  50. 50.
    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.Google Scholar
  51. 51.
    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.PubMedGoogle Scholar
  52. 52.
    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.PubMedGoogle Scholar
  53. 53.
    DiScipio, R. G. and Stura, E. A. (1996) Crystallization of human complement component C5. Mol. Immunol. 33, 43–43 (Abstr).Google Scholar
  54. 54.
    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.CrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    Lachmann, P. J. and Davies, A. (1997) Complement and immunity to viruses. Immunol. Rev. 159, 69–77.PubMedCrossRefGoogle Scholar
  61. 61.
    Cooper, N. R. (1991) Complement evasion strategies of microorganisms. Immunol. Today 12, 327–331.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Kotwal, G. J., and Moss, B. (1988) Vaccinia virus encodes a secretory polypeptide structurally related to complement control proteins. Nature 335, 176–178.PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    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.PubMedCrossRefGoogle Scholar
  67. 67.
    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.PubMedGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    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.Google Scholar
  70. 70.
    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.PubMedGoogle Scholar
  71. 71.
    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.PubMedGoogle Scholar
  72. 72.
    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.PubMedCrossRefGoogle Scholar
  73. 73.
    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.PubMedGoogle Scholar
  74. 74.
    Bruggemann, M. and Taussig, M. J. (1997) Production of human antibody repertoires in transgenic mice. Curr. Opin. Biotechnol. 8, 455–458.PubMedCrossRefGoogle Scholar
  75. 75.
    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.CrossRefGoogle Scholar
  76. 76.
    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).Google Scholar
  77. 77.
    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.Google Scholar
  78. 78.
    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.CrossRefGoogle Scholar
  79. 79.
    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.PubMedCrossRefGoogle Scholar
  80. 80.
    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.PubMedCrossRefGoogle Scholar
  81. 81.
    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.PubMedCrossRefGoogle Scholar
  82. 82.
    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.PubMedCrossRefGoogle Scholar
  83. 83.
    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.PubMedCrossRefGoogle Scholar
  84. 84.
    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.CrossRefGoogle Scholar
  85. 85.
    Reynard, A. M. (1980) The regulation of complement activity by pharmacologic agents. J. Immunopharmacology 2, 1–47.CrossRefGoogle Scholar
  86. 86.
    Johnson, B. J. (1977) Complement: a host defense mechanism ready for pharmacological manipulation? J. Pharmaceut. Sci. 66, 1367–1377.CrossRefGoogle Scholar
  87. 87.
    Makrides, S. C. (1998) Therapeutic inhibition of the complement system. Pharmacol. Rev. 50, 59–87.PubMedGoogle Scholar
  88. 88.
    Asghar, S. S. (1984) Pharmacological manipulation of complement system. Pharmacol. Rev. 36, 223–244.PubMedGoogle Scholar
  89. 89.
    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.PubMedCrossRefGoogle Scholar
  90. 90.
    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.PubMedCrossRefGoogle Scholar
  91. 91.
    Matsushita, M. (1996) The lectin pathway of the complement system. Microbiol. Immunol. 40, 887–893.PubMedGoogle Scholar
  92. 92.
    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.CrossRefGoogle Scholar
  93. 93.
    Kay, B. K., Kurakin, A. V., and Hyde-DeRuyscher, R. (1998) From peptides to drugs via phage display. Drug Discovery Today 3, 370–378.CrossRefGoogle Scholar
  94. 94.
    Scott, J. K. and Smith, G. P. (1990) Searching for peptide ligands with an epitope library. Science 249, 386–390.PubMedCrossRefGoogle Scholar
  95. 95.
    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.PubMedGoogle Scholar
  96. 96.
    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.PubMedCrossRefGoogle Scholar
  97. 97.
    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.PubMedGoogle Scholar
  98. 98.
    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.CrossRefGoogle Scholar
  99. 99.
    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.PubMedGoogle Scholar
  100. 100.
    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.PubMedCrossRefGoogle Scholar
  101. 101.
    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.PubMedCrossRefGoogle Scholar
  102. 101a.
    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.CrossRefGoogle Scholar
  103. 102.
    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.PubMedCrossRefGoogle Scholar
  104. 103.
    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.Google Scholar
  105. 105.
    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.PubMedCrossRefGoogle Scholar
  106. 105.
    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.PubMedCrossRefGoogle Scholar
  107. 106.
    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.PubMedGoogle Scholar
  108. 107.
    Levine, R. P. and Dodds, A. W. (1990) The thiolester bond of C3. Curr. Top. Microbiol. Immunol. 153, 73–82.PubMedCrossRefGoogle Scholar
  109. 108.
    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.PubMedCrossRefGoogle Scholar
  110. 109.
    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.PubMedCrossRefGoogle Scholar
  111. 110.
    Gordon, J., Whitehead, H., and Wormall, A. (1926) The action of ammonia on complement. The fourth component. Biochem. J. 20, 1028–1035.PubMedGoogle Scholar
  112. 111.
    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.PubMedCrossRefGoogle Scholar
  113. 112.
    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.PubMedCrossRefGoogle Scholar
  114. 113.
    Biesecker, G., Dihel, L., Enney, K., and Bendele, R. (1998) Derivation of RNA aptamer inhibitors of human C5. Mol. Immunol. 35, 334.CrossRefGoogle Scholar
  115. 114.
    Ecker, E. E. and Gross, P. (1929) Anticomplementary power of heparin. J. Infect. Dis. 44, 250–253.CrossRefGoogle Scholar
  116. 115.
    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.PubMedCrossRefGoogle Scholar
  117. 116.
    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.CrossRefGoogle Scholar
  118. 117.
    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.PubMedCrossRefGoogle Scholar
  119. 118.
    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.PubMedCrossRefGoogle Scholar
  120. 119.
    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.PubMedCrossRefGoogle Scholar
  121. 120.
    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.PubMedGoogle Scholar
  122. 121.
    Sahu, A. and Pangburn, M. K. (1993) Identification of multiple sites of interaction between heparin and the complement system. Mol. Immunol. 30, 679–684.PubMedCrossRefGoogle Scholar
  123. 122.
    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.PubMedCrossRefGoogle Scholar
  124. 123.
    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.PubMedCrossRefGoogle Scholar
  125. 124.
    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.PubMedCrossRefGoogle Scholar
  126. 125.
    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.PubMedGoogle Scholar
  127. 126.
    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.PubMedCrossRefGoogle Scholar
  128. 127.
    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, 421–424PubMedCrossRefGoogle Scholar
  129. 128.
    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.PubMedCrossRefGoogle Scholar
  130. 129.
    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.PubMedCrossRefGoogle Scholar
  131. 130.
    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.PubMedCrossRefGoogle Scholar
  132. 131.
    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.CrossRefGoogle Scholar
  133. 132.
    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.PubMedCrossRefGoogle Scholar
  134. 133.
    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.PubMedCrossRefGoogle Scholar
  135. 134.
    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.PubMedGoogle Scholar
  136. 135.
    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.PubMedGoogle Scholar
  137. 136.
    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.Google Scholar
  138. 137.
    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.PubMedCrossRefGoogle Scholar
  139. 138.
    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.Google Scholar
  140. 139.
    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, 713–718PubMedCrossRefGoogle Scholar
  141. 140.
    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.PubMedCrossRefGoogle Scholar
  142. 141.
    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.PubMedCrossRefGoogle Scholar
  143. 142.
    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.CrossRefGoogle Scholar
  144. 143.
    Grindley, J. N. and Ogden, J. E. (1995) Forecasting the future for protein drugs. Scrip. Mag. November, 53–56.Google Scholar
  145. 144.
    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.PubMedCrossRefGoogle Scholar
  146. 145.
    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.Google Scholar
  147. 146.
    Ryan, U. S. (1995) Complement inhibitory therapeutics and xenotransplantation. Nat . Med. 1, 967–968.PubMedCrossRefGoogle Scholar
  148. 147.
    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.PubMedCrossRefGoogle Scholar
  149. 148.
    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.PubMedCrossRefGoogle Scholar
  150. 149.
    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.PubMedCrossRefGoogle Scholar
  151. 150.
    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. 175,1547–1551PubMedCrossRefGoogle Scholar
  152. 151.
    Whaley, K., and Ruddy, S. (1976) Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193, 1011–1013.PubMedCrossRefGoogle Scholar
  153. 152.
    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.PubMedCrossRefGoogle Scholar
  154. 153.
    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.PubMedCrossRefGoogle Scholar
  155. 154.
    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.PubMedGoogle Scholar
  156. 155.
    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.PubMedCrossRefGoogle Scholar
  157. 156.
    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.PubMedGoogle Scholar
  158. 157.
    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.PubMedCrossRefGoogle Scholar
  159. 158.
    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.PubMedGoogle Scholar
  160. 159.
    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.Google Scholar
  161. 160.
    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.Google Scholar
  162. 161.
    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.PubMedGoogle Scholar
  163. 162.
    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.PubMedGoogle Scholar
  164. 163.
    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.PubMedGoogle Scholar
  165. 164.
    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.PubMedGoogle Scholar
  166. 165.
    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.PubMedCrossRefGoogle Scholar
  167. 166.
    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.CrossRefGoogle Scholar
  168. 167.
    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.PubMedCrossRefGoogle Scholar
  169. 167a.
    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.PubMedGoogle Scholar
  170. 168.
    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.PubMedGoogle Scholar
  171. 169.
    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.CrossRefGoogle Scholar
  172. 170.
    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.PubMedGoogle Scholar
  173. 171.
    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.PubMedGoogle Scholar
  174. 172.
    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.PubMedCrossRefGoogle Scholar
  175. 173.
    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.CrossRefGoogle Scholar
  176. 174.
    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.Google Scholar
  177. 175.
    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.PubMedCrossRefGoogle Scholar
  178. 176.
    Ikari, N., Sakai, Y., Hitomi, Y., and Fujii, S. (1983) New synthetic inhibitor to the alternative complement pathway. Immunology 49, 685–691.PubMedGoogle Scholar
  179. 177.
    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.PubMedCrossRefGoogle Scholar
  180. 178.
    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.PubMedCrossRefGoogle Scholar
  181. 179.
    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.PubMedCrossRefGoogle Scholar
  182. 180.
    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.PubMedCrossRefGoogle Scholar
  183. 181.
    Quigg, R. J. (1992) Inhibition of the alternative pathway of complement by glomerular chondroitin sulphate proteoglycan. Immunology 76, 373–377PubMedGoogle Scholar
  184. 182.
    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.Google Scholar
  185. 183.
    Jansen, J. A. (1969) A specific inactivator of mammalian C’4 isolated from nurse shark (Ginglymostroma cirratum) serum. J. Exp. Med. 130, 217–241.CrossRefGoogle Scholar
  186. 184.
    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.CrossRefGoogle Scholar
  187. 185.
    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.PubMedCrossRefGoogle Scholar
  188. 186.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2000

Authors and Affiliations

  • Arvind Sahu
  • Dimitrios Morikis
  • John D. Lambris

There are no affiliations available

Personalised recommendations