compstatin and Hemolysis

compstatin has been researched along with Hemolysis* in 9 studies

*Hemolysis: The destruction of ERYTHROCYTES by many different causal agents such as antibodies, bacteria, chemicals, temperature, and changes in tonicity. [MeSH]

Reviews

1 review(s) available for compstatin and Hemolysis

ArticleYear
Compstatins: the dawn of clinical C3-targeted complement inhibition.
    Trends in pharmacological sciences, 2022, Volume: 43, Issue:8

    Despite the growing recognition of the complement system as a major contributor to a variety of clinical conditions, the therapeutic arsenal has remained scarce. The introduction of an anti-C5 antibody in 2007 raised confidence in complement-targeted therapy. However, it became apparent that inhibition of late-stage effector generation might not be sufficient in multifactorial complement disorders. Upstream intervention at the level of C3 activation has therefore been considered promising. The approval of pegcetacoplan, a C3 inhibitor of the compstatin family, in 2021 served as critical validation of C3-targeted treatment. This review delineates the evolution of the compstatin family from its academic origins to the clinic and highlights current and potential future applications of this promising drug class in complement diseases.

    Topics: Antibodies, Monoclonal, Humanized; Complement C3; Complement System Proteins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Peptides, Cyclic

2022

Other Studies

8 other study(ies) available for compstatin and Hemolysis

ArticleYear
Complement C3 inhibition by compstatin Cp40 prevents intra- and extravascular hemolysis of red blood cells.
    Haematologica, 2020, Volume: 105, Issue:2

    Topics: Complement Activation; Complement C3; Erythrocytes; Hemolysis; Humans; Peptides, Cyclic

2020
In vitro Inhibition of Canine Complement-Mediated Hemolysis.
    Journal of veterinary internal medicine, 2018, Volume: 32, Issue:1

    Immune-mediated hemolytic anemia (IMHA) is the most common hematologic immune-mediated disease in dogs. Complement fixation on erythrocytes causes hemolysis. Complement inhibition decreases hemolysis in people with the hemolytic disease and also may prove effective in treating IMHA in dogs.. Evaluate the in vitro efficacy of 2 complement inhibitors used in humans against canine complement.. The inhibitory activity of the C3-inhibitor compstatin and recombinant human C1-esterase inhibitor (C1-INH) was evaluated using an in vitro hemolytic assay and spectrophotometric measurement of released hemoglobin. Dose-response curves for each inhibitor were generated.. Compstatin decreased approximately 50% of canine complement-mediated hemolysis in initial experiments. This inhibition largely was lost when a new lot of drug was purchased. C1-INH showed a dose-dependent inhibition. The highest concentration of C1-INH tested (500 μg/mL) decreased >80% of canine complement-mediated hemolysis, and the lowest concentration tested (31.25 μg/mL) decreased hemolysis >60%.. Human C1-INH is a robust inhibitor of canine complement-mediated hemolysis, whereas compstatin was minimally and variably effective. Human C1-INH may substantially decrease complement-mediated hemolysis in dogs with IMHA and warrants further investigation.

    Topics: Animals; Complement C1 Inhibitor Protein; Complement Inactivating Agents; Dogs; Erythrocytes; Hemolysis; Peptides, Cyclic; Recombinant Proteins; Sheep

2018
Peptide redesign for inhibition of the complement system: Targeting age-related macular degeneration.
    Molecular vision, 2016, Volume: 22

    To redesign a complement-inhibiting peptide with the potential to become a therapeutic for dry and wet age-related macular degeneration (AMD).. We present a new potent peptide (Peptide 2) of the compstatin family. The peptide is developed by rational design, based on a mechanistic binding hypothesis, and structural and physicochemical properties derived from molecular dynamics (MD) simulation. The inhibitory activity, efficacy, and solubility of Peptide 2 are evaluated using a hemolytic assay, a human RPE cell-based assay, and ultraviolet (UV) absorption properties, respectively, and compared to the respective properties of its parent peptide (Peptide 1).. The sequence of Peptide 2 contains an arginine-serine N-terminal extension (a characteristic of parent Peptide 1) and a novel 8-polyethylene glycol (PEG) block C-terminal extension. Peptide 2 has significantly improved aqueous solubility compared to Peptide 1 and comparable complement inhibitory activity. In addition, Peptide 2 is more efficacious in inhibiting complement activation in a cell-based model that mimics the pathobiology of dry AMD.. We have designed a new peptide analog of compstatin that combines N-terminal polar amino acid extensions and C-terminal PEGylation extensions. This peptide demonstrates significantly improved aqueous solubility and complement inhibitory efficacy, compared to the parent peptide. The new peptide overcomes the aggregation limitation for clinical translation of previous compstatin analogs and is a candidate to become a therapeutic for the treatment of AMD.

    Topics: Amino Acid Sequence; Animals; Cell Line; Complement System Proteins; Hemolysis; Humans; Inhibitory Concentration 50; Macular Degeneration; Peptides; Peptides, Cyclic; Rabbits; Solubility

2016
New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.
    Journal of medicinal chemistry, 2015, Jan-22, Volume: 58, Issue:2

    Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with α-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.

    Topics: Amino Acid Sequence; Animals; Cells, Cultured; Complement Inactivating Agents; Hemolysis; Humans; Molecular Sequence Data; Peptides, Cyclic; Rabbits; Retinal Pigment Epithelium; Solubility

2015
Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria.
    Blood, 2014, Mar-27, Volume: 123, Issue:13

    Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the lack of CD55 and CD59 on affected erythrocytes. The anti-C5 antibody eculizumab has proven clinically effective, but uncontrolled C3 activation due to CD55 absence may result in opsonization of erythrocytes, possibly leading to clinically meaningful extravascular hemolysis. We investigated the effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system. Both compounds demonstrated dose-dependent inhibition of hemolysis with IC50 ∼4 µM and full inhibition at 6 µM. Protective levels of either Cp40 or PEG-Cp40 also efficiently prevented deposition of C3 fragments on PNH erythrocytes. We further explored the potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates. A single intravenous injection of PEG-Cp40 resulted in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration. In conclusion, peptide inhibitors of C3 activation effectively prevent hemolysis and C3 opsonization of PNH erythrocytes, and are excellent, and potentially cost-effective, candidates for further clinical investigation.

    Topics: Animals; Complement Activation; Complement C3; Drug Design; Erythrocytes; Half-Life; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Macaca fascicularis; Peptide Fragments; Peptides, Cyclic; Polyethylene Glycols

2014
Structure-activity relationships for substrate-based inhibitors of human complement factor B.
    Journal of medicinal chemistry, 2009, Oct-08, Volume: 52, Issue:19

    Human complement is a cascading network of plasma proteins important in immune defense, cooperatively effecting recognition, opsonization, destruction, and removal of pathogens and infected/damaged cells. Overstimulated or unregulated complement activation can result in immunoinflammatory diseases. Key serine proteases in this cascade are difficult to study due to their multiprotein composition, short lifetimes, formation on membranes, or serum circulation as inactive zymogens. Factor B is inactive at pH 7, but a catalytically active serine protease under alkaline conditions, enabling structure-activity relationship studies for 63 substrate-based peptide inhibitors with 4-7 residues and a C-terminal aldehyde. A potent factor B inhibitor was hexpeptide Ac-RLTbaLAR-H (IC(50) 250 nM, pH 9.5), which at pH 7 also blocked formation of membrane attack complex via the "alternative pathway" of complement activation and inhibited human complement mediated lysis of rabbit erythrocytes. Inhibitors of factor B may be valuable probes and drug leads for complement mediated immunity and disease.

    Topics: Animals; Complement Activation; Complement Factor B; Complement Pathway, Alternative; Erythrocytes; Hemolysis; Humans; Molecular Mimicry; Oligopeptides; Rabbits; Structure-Activity Relationship

2009
C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl alpha-ketoheterocycles.
    Immunopharmacology, 2000, Jul-20, Volume: 48, Issue:2

    C3 convertase is a key enzyme in the complement cascade and is an attractive therapeutic target for drug design. Recent studies have demonstrated that this enzyme is inhibited by compstatin (Morikis, D. , Assa-Munt, N., Sahu, A., Lambris, J.D., 1998. Solution structure of Compstatin, a potent complement inhibitor. Protein Sci. (7) 619-627; Sahu, A., Kay, B.K., 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), a 13 amino acid cyclic peptide that binds to C3. Since the enzyme exhibits some homology to serine proteases, substrate-based design could be another avenue for drug design. In this study, we confirm the activity of compstatin using different sources of enzyme and different assay systems. We also tested the activity of substituted compstatin analogs and compared the selectivity and toxicity of these compounds to peptidyl alpha-ketoheterocyclic compounds. Our work confirms the activity of compstatin in both alternative and classical complement pathways, describes 11 new active analogs of this cyclic peptide, and provides evidence for key segments of the peptide for activity. Compstatin and related active analogs showed little or no inhibition of clotting or key enzymes in the clotting cascade nor did they appear to have significant cytotoxicity. The characteristics of compstatin suggest that this peptide and its analogs could be attractive candidates for further clinical development. By contrast, known serine protease inhibitors, including peptidyl alpha-ketoheterocycles, did not inhibit C3 convertase illustrating the atypical nature of this enzyme.

    Topics: Complement Activation; Complement C3; Complement C3-C5 Convertases; Complement Factor B; Complement Inactivator Proteins; Hemolysis; Humans; Immunoenzyme Techniques; Peptides, Cyclic; Serine Proteinase Inhibitors

2000
Binding kinetics, structure-activity relationship, and biotransformation of the complement inhibitor compstatin.
    Journal of immunology (Baltimore, Md. : 1950), 2000, Sep-01, Volume: 165, Issue:5

    We have previously identified a 13-residue cyclic peptide, Compstatin, that binds to complement component C3 and inhibits complement activation. Herein, we describe the binding kinetics, structure-activity relationship, and biotransformation of Compstatin. Biomolecular interaction analysis using surface-plasmon resonance showed that Compstatin bound to native C3 and its fragments C3b and C3c, but not C3d. While binding of Compstatin to native C3 was biphasic, binding to C3b and C3c followed the 1:1 Langmuir binding model; the affinities of Compstatin for C3b and C3c were 22- and 74-fold lower, respectively, than that of native C3. Analysis of Compstatin analogs synthesized for structure-function studies indicated that 1) the 11-membered ring between disulfide-linked Cys2-Cys12 constitutes a minimal structure required for optimal activity; 2) retro-inverso isomerization results in loss of inhibitory activity; and 3) some residues of the type I beta-turn segment also interact with C3. In vitro studies of Compstatin in human blood indicated that a major pathway of biotransformation was the removal of Ile1, which could be blocked by N-acetylation of the peptide. These findings indicate that acetylated Compstatin is stable against enzymatic degradation and that the type I beta-turn segment is not only critical for preservation of the conformational stability, but also involved in intermolecular recognition.

    Topics: Amino Acid Sequence; Arginine; Biotransformation; Complement C3; Complement Inactivator Proteins; Cysteine; Hemolysis; Humans; Hydrolysis; Kinetics; Molecular Sequence Data; Peptide Fragments; Peptides, Cyclic; Protein Binding; Structure-Activity Relationship

2000