Inhibition of Heparin/Protamine Complex-Induced Complement Activation by Compstatin in Baboons

Soulika, Athena M.; Khan, Mohammad M.; Hattori, Takashi; Bowen, Frank W.; Richardson, Brian A.; Hack, C. E.; Sahu, Arvind; Edmunds, L. Henry; Lambris, John D.

doi:10.1006/clim.2000.4903

Cited by 65 publications

(40 citation statements)

References 42 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…61 It has been tested in several animal models and shown to be an effective complement inhibitor. 62,63 Recently, Risitano and co-workers elegantly demonstrated that pegylated compstatin not only efficiently prevents lysis of PNH-RBCs, but also C3 deposition. 64 Currently, compstatin is being tested in a human clinical trial for age-related macular degeneration (AMD) and in pre-clinical studies for several other inflammatory diseases.…”

mentioning

confidence: 99%

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

View full text Add to dashboard Cite

© F e r r a t a S t o r t i F o u n d a t i o n Complement systemThe complement system is an evolutionary highly conserved cascade system that makes up part of the innate immune system. [7][8][9] Complement activation can occur via three distinct pathways (classical pathway (CP), lectin pathway (LP) and alternative pathway (AP) that converge at the level of C3 cleavage and eventually lead to a common terminal pathway (TP) ( Figure 1A).The AP can be initiated by spontaneous hydrolysis of the central complement component into C3b(H 2 O). C3b(H 2 O) is an acceptor for the next AP protein Factor B (FB) which is then cleaved by the serine protease factor D (FD), resulting Complement inhibition in AIHA haematologica | 2015; 100 (11) 1389 The lectin pathway is initiated by binding of MBL (or ficolins) to sugar structures followed by activation of C2 and C4 by MASP1/MASP2, leading to the formation of lectin C3 convertase (C2aC4b). (E) C3-activation by the classical, lectin or alternative C3 convertase results in the formation of the C5 convertase. C5 convertase subsequently activates C5 resulting in the formation of the membrane attack complex (MAC). C: complement factor; MAC: membrane attack complex; MBL: mannan binding lectin; MASP: MBL-associated serine protease; P: properdin; C1-inh: C1-inhibitor; FI: factor I; CR1: complement receptor 1; MCP: membrane co-factor protein; DAF: decay accelerating factor; C4BP: C4-binding protein; FH: factor H. A B C D E © F e r r a t a S t o r t i F o u n d a t i o nin the fluid phase C3 convertase (C3b(H 2 O)Bb), that can cleave multiple C3 molecules into C3b and C3a. C3b binds to nucleophilic targets on cell membranes 10 and C3a acts as a pro-inflammatory anaphylatoxin ( Figure 1B). Low-level activation of C3 can significantly be accelerated through a positive feedback loop resulting in the formation of additional alternative C3 convertases on the surface (C3bBb) that are stabilized by properdin (P) and eventually give rise to the formation of a C5 convertase (C3bBbC3b), which subsequently cleaves C5 into C5b and C5a.10 C5b attaches to the surface and subsequently binds to C6, C7 and C8 to form the C5bC8 complex allowing polymerization of C9 to form the membrane attack complex (MAC), which inserts into target membranes and induces cell lysis ( Figure 1A and E). 11,12 Next to lysis by the MAC, cleavage of both C3 and C5 results in the generation of pro-inflammatory anaphylatoxins (C3a, C5a) that attract and activate leukocytes 13 and C3b opsonization of the target surface facilitates uptake by phagocytic cells in the liver and spleen.During evolution complement activation became more specific by the development of recognition molecules. The CP is initiated by binding of C1q to the Fc-part of IgM or IgG complexed with their target antigens. IgM is most efficient in complement activation, due to its polymeric nature. Human IgG activates complement in the order IgG3>IgG1>IgG2, whereas IgG4 does not activate complement at all.14 As the affinity of C1q for a single IgG Fc tail is...

show abstract

mentioning

confidence: 99%

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Wouters

2015

Haematologica

View full text Add to dashboard Cite

show abstract

“…5). For example, compstatin was shown to prolong the survival of kidneys in an ex vivo xenograft model (7), inhibited complement activation during the contact of whole blood with biomaterial in a model of extracorporeal circulation (8), and inhibited in vivo complement activation in a non-human primate model of heparin-protamine complex-induced inflammation resembling heart surgery (9). Compstatin displayed an inhibitory activity of IC 50 ϭ 12 M. In solution, compstatin forms a ␤-turn at residues Gln-5-Gly-8 with the disulfide bridge Cys-2-Cys-12, residues Ile-1-Val-4, and Thr-13, forming a hydrophobic cluster (10,11).…”

mentioning

confidence: 99%

Structure of Compstatin in Complex with Complement Component C3c Reveals a New Mechanism of Complement Inhibition

Janssen

Halff

Lambris

et al. 2007

Journal of Biological Chemistry

Self Cite

119

249

View full text Add to dashboard Cite

Undesired complement activation is a major cause of tissue injury in various pathological conditions and contributes to several immune complex diseases. Compstatin, a 13-residue peptide, is an effective inhibitor of the activation of complement component C3 and thus blocks a central and crucial step in the complement cascade. The precise binding site on C3, the structure in the bound form, and the exact mode of action of compstatin are unknown. Here we present the crystal structure of compstatin in complex with C3c, a major proteolytic fragment of C3. The structure reveals that the compstatin-binding site is formed by the macroglobulin (MG) domains 4 and 5. This binding site is part of the structurally stable MG-ring formed by domains MG 1-6 and is far away from any other known binding site on C3. Compstatin does not alter the conformation of C3c, whereas compstatin itself undergoes a large conformational change upon binding. We propose a model in which compstatin sterically hinders the access of the substrate C3 to the convertase complexes, thus blocking complement activation and amplification. These insights are instrumental for further development of compstatin as a potential therapeutic.The complement system is a key part of the innate and adaptive immune system and plays a major role in homeostasis by clearing altered host cells and invading pathogens (1, 2). Inappropriate activation of the complement system leads to tissue injury, causing or aggravating various pathological conditions, such as autoimmune diseases, burn injuries, Alzheimer disease, stroke, and heart attack (reviewed in Ref.3). Several complement inhibitors are under development, targeting various steps in the complement activation pathways. None of these compounds have been approved for clinical use yet (3-5). We studied a 13-residue cyclic peptide, called compstatin, which inhibits complement response by preventing the proteolytic activation of C3 3 (6). Activation of C3 by the C3 convertases is a central amplification step in complement activation. All three recognition and initiation pathways, the classical, lectin, and alternative pathways, converge in the activation of C3. Proteolytic activation of C3 yields C3b, which covalently binds to pathogenic or self surfaces, providing a strong signal for clearance of the tagged particles. Because compstatin blocks this critical step of complement activation and because it is a small non-immunogenic peptide, compstatin has the potential to be developed into a therapeutic agent.Compstatin (ICVVQDWGHHRCT-NH 2 , circularized by disulfide bond Cys-2-Cys-12) was discovered by a phage-display, random peptide library search (6). Compstatin has been shown to be an effective inhibitor of complement activation in several clinically relevant models (reviewed in Ref. 5). For example, compstatin was shown to prolong the survival of kidneys in an ex vivo xenograft model (7), inhibited complement activation during the contact of whole blood with biomaterial in a model of extracorporeal circulation (8), and in...

show abstract

“…In the xenotransplantation model, compstatin significantly prolonged the survival of the kidneys (2), whereas in the models of extracorporeal circulation it inhibited the generation of C3a and sC5b-9 and activation of polymorphonuclear leukocytes (3). The efficacy of compstatin has also been evaluated in an in vivo model of complement activation in baboons (4). In this model, compstatin completely inhibited complement activation and exhibited no toxic effects in all doses tested, suggesting that it may be both a safe and effective complement inhibitor.…”

mentioning

confidence: 99%

“…Compstatin forms a type I ␤-turn in the region Gln 5 -Asp 6 -Trp 7 -Gly 8 . In addition, compstatin possesses a hydrophobic cluster at the opposite side of the ␤-turn involving residues at the linked termini Ile 1 -Cys 2 -Val 3 -Val 4 -Cys 12 -Thr 13 . An Ala scan indicated that the amino acids Cys 2 , Val 3 , and Cys 12 of the hydrophobic cluster and the amino acids of the ␤-turn are essential for the activity of compstatin in vitro (8,10).…”

mentioning

confidence: 99%

Studies of Structure-Activity Relations of Complement Inhibitor Compstatin

Soulika

Morikis

Sarrias

et al. 2003

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Compstatin, a 13-mer cyclic peptide, is a novel and promising inhibitor of the activation of the complement system. In our search for a more active analog and better understanding of structure-functions relations, we designed a phage-displayed random peptide library based on previous knowledge of structure activity relations, in which seven amino acids deemed necessary for structure and activity were kept fixed while the remaining six were optimized. Screening of this library against C3 identified four binding clones. Synthetic peptides corresponding to these clones revealed one analog, called acetylated Ile1Leu/His9Trp/Thr13Gly triple replacement analog of compstatin corresponding to clone 640 (Ac-I1L/H9W/T13G), which was more active than compstatin. This newly identified peptide had 4-fold higher activity when compared with the originally isolated form of compstatin and 1.6-fold higher activity when compared with acetylated compstatin (Ac-compstatin). The structures of Ac-I1L/H9W/T13G and Ac-compstatin were studied by nuclear magnetic resonance, compared with the structure of compstatin, and found to be very similar. The binding of Ac-I1L/H9W/T13G and the equally active acetylated analog with His9Ala replacement (Ac-H9A) to C3 was evaluated by surface plasmon resonance, which suggested similarity in their binding mechanism but difference when compared with Ac-compstatin. Compensatory effects of flexibility outside the β-turn and tryptophan ring stacking may be responsible for the measured activity increase in Ac-I1L/H9W/T13G and acetylated analog with His9Ala replacement and the variability in binding mechanism compared with Ac-compstatin. These data demonstrate that tryptophan is a key amino acid for activity. Finally, the significance of the N-terminal acetylation was examined and it was found that the hydrophobic cluster at the linked termini of compstatin is essential for binding to C3 and for activity.

show abstract

Inhibition of Heparin/Protamine Complex-Induced Complement Activation by Compstatin in Baboons

Cited by 65 publications

References 42 publications

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Complement inhibitors to treat IgM-mediated autoimmune hemolysis

Structure of Compstatin in Complex with Complement Component C3c Reveals a New Mechanism of Complement Inhibition

Studies of Structure-Activity Relations of Complement Inhibitor Compstatin

Contact Info

Product

Resources

About