Peptides which inhibit complement activation

Details Peptides which inhibit complement activation Peptides which inhibit complement activation

1999-02-01

2001-11-20

Romeo, David (Department: 1647)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C514S014800, C514S015800, C530S300000, C530S317000, C530S324000, C530S327000, C930S260000

Reexamination Certificate

active

06319897

ABSTRACT:

BACKGROUND OF THE INVENTION
Complement is a group of related plasma proteins that participate in inflammatory reactions. The activation of complement by classical and alternative pathways generates kinins from platelets, eosinophils and neutrophils. This activation is important in phagocytosis and curtailing infection.
Although complement is an important line of defense against pathogenic organisms, its activation can also lead to host cell damage. Complement-mediated tissue injury has been reported in a wide variety of diseases, including autoimmune diseases such as experimental allergic neuritis (Vriesendorp et al.
J. Neuroimmunol.
1995 58:157), type II collagen-induced arthritis (Watson, W. C. and A. S. Townes,
J. Exp. Med.
1985 162:1878), myasthenia gravis (Nakano, S. and A. G. Engel,
Neurology
1993 43:1167; Barohn, R. J. and R. L. Brey,
Clin. Neurol. Neurosurg.
1993 95:285), hemolytic anemia (Schreiber, A. D. and M. M. Frank,
J. Clin. Invest.
1972 51:575), glomerulonephritis (McLean, R. H.
Pediatr. Nephrol.
1993 7:226), and immune complex-induced vasculitis (Cochrane, C. G.
Springer Semin. Immunopathol.
1984 7:263). It has also been identified in the adult respiratory distress syndrome (Robbins et al.
Am. Rev. Respir. Dis.
1987 135:651), stroke (Vasthare et al.
FASEB J.
1993 7:A424), heart attack (Kilgore et al.
Cardiovasc. Res.
1994 28:437), xenotransplantation (Wang et al.
Histochem . J.
1992 24:102; Leventhal et al.
Transplantation
1993 55:857), multiple sclerosis (Williams et al.
Clin. Neurosci.
1994 2:229), burn injuries (Gallinaro et al.
Surg. Gynecol. Obstet.
1992 174:435), extracorporeal dialysis and blood oxygenation (Pekna et al.
Clin. exp. Immunol.
1993 91:404).
The third complement component, C3, is known to have an important role in both classical and alternative pathways of complement activation. Proteolytic activation of C3 by classical (C4b,2a) or alternative (C3b,Bb) pathway C3 convertase leads to cleavage of C3 into an anaphylotoxic peptide C3a and an opsonic fragment C3b. Covalent attachment of metastable C3b to target cells undergoing complement attack results in generation of C5a and formation of C5b-9 membrane attack complex. However, the tissue injury that results from complement activation is directly mediated by the membrane attack complex, C5b-C9, and indirectly by the generation of anaphylotoxic peptides C3a and C5a. These peptides induce damage through their effect on neutrophils and mast cells. Upon stimulation with C5a, neutrophils produce a serine elastase that causes tissue injury. C5a also triggers the generation of toxic oxygen-derived free radicals from neutrophils, and both C3a and C5a stimulate rapid and enhanced production of leukotrienes from IL-3-primed basophils.
Control of the activation process is mediated in vivo by a family of structurally and functionally related proteins termed regulators of complement activation (hereinafter referred to as RCA). The RCA include both plasma proteins, i.e. factor H and C4 binding protein (C4bp) and membrane proteins, i.e., complement receptor 1 (CR1), decay-accelerating factor (DAF) and membrane cofactor protein (MCP). These proteins inhibit the generation of C3a and C5a by inactivating the C3 and C5 convertases of the classical and alternative pathways. Inhibition of complement activation by these proteins is achieved by dissociation of the subunits of C3 and C5 convertases and/or by proteolytic inactivation of the subunits by factor I.
The importance of complement-mediated tissue injury via a wide variety of disease states underscores the growing need for a specific complement inhibitor. Various approaches have been used to identify such an inhibitor. These include targeting the serine proteases with peptides or chemical compounds. PCT/US95/02945 disclose chimeric complement inhibitor proteins having a first functional domain with C3 inhibitory activity and a second functional domain with C5b-9 inhibitory activity. More recently attempts have been made to target the thioester of C3. For example, salicyl hydroxamate, believed to be one of the most potent inhibitors of C3, inhibits complement by reacting with the thioester of C3 (Sim et al.
Biochem. J.
1981 193:115). The 50% inhibitory concentrations required for the inhibition of classical and alternative pathway-mediated hemolytic activities with this compound were 280 &mgr;M and 33 &mgr;M, respectively. However, salicyl hydroxamate has been reported to produce systemic lupus erythematosus-like syndrome as a toxic side effect (Sim et al.
Lancet
1984 ii:422). Kalli et al. demonstrated that a soluble form of CR1 (sCR
1
) suppresses complement in several complement-dependent disease models (
Springer Semin. Immunopathol.
1994 15:417).
In the present invention, peptides that inhibit complement activation have been identified and synthesized.
SUMMARY OF THE INVENTION
An object of the present invention is to provide peptides and peptide analogs that inhibit complement activation. Exemplary peptides of the present invention comprise at least a portion of the amino acid sequence of the N-terminal cyclic region of a peptide of SEQ ID NO: 1. In a preferred embodiment, the peptides of the present invention comprise at least the 13 amino acid sequence of SEQ ID NO: 2.
Yet another object of the present invention is to provide a method of producing compositions, such as peptide analogs or peptidomimetics, capable of inhibiting complement activation which comprises identifying the conformation of a peptide having SEQ ID NO: 1 or SEQ ID NO: 2, which is capable of interacting with C3 to inhibit complement activation, and producing a composition having a sufficiently similar conformation so that the composition interacts with C3 to inhibit complement activation.
Yet another object of the present invention is to provide a composition having sufficiently similar conformation to the peptide having SEQ ID NO: 1 or SEQ ID NO: 2 such that the composition is capable of interacting with C3 to inhibit complement activation. Examples of such compositions include peptide analogs of SEQ ID NO: 1 or SEQ ID NO: 2, having conservative amino acid substitutions, i.e. substitutions that do not materially alter the structure of the analog as compared to SEQ ID NOS: 1 or 2, and having complement-inhibiting activity. Other examples include peptidomimetics having sufficiently similar conformation to SEQ ID NOS: 1 or 2 so as to exhibit complement-inhibiting activity.
Another object of the present invention is to provide a method of inhibiting complement activation in a patient comprising administering to a human an effective amount of a peptide of the present invention.
Yet another object of the present invention is to provide a method treating complement-mediated tissue injury in a patient comprising administering to a patient an effective amount of a peptide of the present invention.
Yet another object of the present invention is to provide a method of inhibiting complement activation which occurs during use of artificial organs or implants which comprises coating the artificial organ or implant with a peptide of the present invention.
Yet another object of the present invention is to provide a method of inhibiting complement activation that occurs during extracorporeal shunting of physiological fluids (e.g. blood, urine), which comprises coating the tubing through which said fluids are shunted with a peptide of the present invention.


REFERENCES:
patent: 5256642 (1993-10-01), Fearon et al.
Bowie et al. Deciphering the message in protein sequences: tolerance to amino acid substitutions. Science, (Mar. 16, 1990) 247 (4948) 1306-10.*
Ngo et al., in The Protein Folding Problem and Tertiary Structure Prediction, Merz and Le Grand (Eds), Aug. 1994, Springer Verlag, pp. 433 and 492-495.*
Kalli, K.R. et al., 1994, Therapeutic uses of recombinant protein inhibitors. Springer Semin. Immunopathol. 15:417-431.
Schasteen C.S. et al., 1991, Synthetic peptide inhibitors of complement serine proteases—III. Significant increase in inhibitor potency provides f

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