Therapeutic uses of recombinant complement protein inhibitors

Kalli, Kimberly R.; Hsu, Peihong; Fearon, Douglas T.

doi:10.1007/bf01837368

Cited by 59 publications

(27 citation statements)

References 107 publications

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“…In fact, many physiological regulators of complement, e.g., factor H, CRI, DAF, and MCP, act on C3b to inhibit complement activation. A soluble form of CRl has been tested and found to suppress complement pathology in a number of in vivo complement-dependent diseases models (Kalli et al, 1994). HOWever, identifying a smaller biologically active fragment of these regulatory proteins or a peptide mimetic is necessary for structural studies and the rational design of a clinical drug.…”

Section: Biological Significance and Structural Determinants Importanmentioning

confidence: 99%

“…These proteins inhibit the C3 and C5 convertases (multisubunit proteases) by promoting dissociation of the multisubunit complexes and/or by inactivating the complexes through proteolysis (catalyzed by factor I). Several pharmacological agents that regulate or modulate complement activity have been identified by in vitro assay, but most have been shown to be of low activity or toxic (Johnson, 1977;Reynard, 1980;Kalli et al, 1994;Morgan, 1994).…”

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confidence: 99%

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Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3JNH.H,-~o~pling constant restraints. The Compstatin structure contained a type I p-turn comprising the segment GlnS-Asp6-Trp7-Glys. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp' was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3JNH.H,-~o~pling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, G l d , Asp6, Trp7, and Glys contribute significantly to the inhibitory activity of the peptide. Substitution of Gly' caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His', His", and Arg" resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the &turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.The complement system is the first line of immunological defense against foreign pathogens (Muller-Eberhard, 1992). Its activation through the classical, alternative, or lectin pathways leads to the generation of anaphylatoxic peptides C3a and C5a and formation of the C5b-9 membrane attack complex. Complement component C3 plays a central role in activation of all three pathways. Activation of C3 by complement pathway C3 convertases and its subsequent attachment to target surface leads to assembly of the membrane attack complex and ultimately to damage or lysis of the target cells (Frank & Fries, 1991). C3 is unique in that it possesses Reprint requests to:

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Section: Biological Significance and Structural Determinants Importanmentioning

confidence: 99%

mentioning

confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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“…The most common variant's extramembraneous portion is composed of 30 SCRs and has one copy of SITE 1 and two copies of SITE 2 [2]. SITE 1, with SCRs 1-4, binds mainly C4b, while SITE 2, with SCRs 8-11 and duplicated in SCRs 15-18, is implicated predominantly in C3b binding [2][3][4][5][6].…”

Section: Binding Sites On Crl For C3b/c4bmentioning

confidence: 99%

Complement receptors and regulatory proteins: immune adherence revisited and abuse by microorganisms

Atkinson

Krych

Nickells

et al. 1994

Clinical and Experimental Immunology

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“…However, this problem (7). in addition to having extended piasma half-lives, 0R1 -ig chimeras with appropriate antibody specifities could be targeted to certain sites at which complement activation was occurring.…”

Section: Soluble Cr1 As An Inhibitor Of Complement Activationmentioning

confidence: 99%

Anti-Inflammatory and Immunosuppressive Effects of Recombinant Soluble Complement Receptors

Dt¹

1991

Clinical and Experimental Immunology

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Therapeutic uses of recombinant complement protein inhibitors

Cited by 59 publications

References 107 publications

Solution structure of Compstatin, a potent complement inhibitor

Solution structure of Compstatin, a potent complement inhibitor

Complement receptors and regulatory proteins: immune adherence revisited and abuse by microorganisms

Anti-Inflammatory and Immunosuppressive Effects of Recombinant Soluble Complement Receptors

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