C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl α-ketoheterocycles

Furlong, Stephen T.; Dutta, Anand S.; Coath, Matthew; Gormley, James J.; Hubbs, Stephen J.; Lloyd, Darleen; Mauger, Russell C.; Strimpler, Anne M.; Sylvester, Mark; Scott, Clay W.; Edwards, Philip D.

doi:10.1016/s0162-3109(00)00205-8

Cited by 34 publications

(48 citation statements)

References 41 publications

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“…NIH-PA Author Manuscript NIH-PA Author Manuscript pathway has later been confirmed and further investigated by independent groups from both academic research and pharmaceutical industry (Furlong et al 2000;Klegeris et al 2002).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 83%

“…In situ formation of the C3 convertase on a SPR sensor chip further revealed that compstatin indeed inhibited the formation and deposition of active C3b when it was co-injected with C3 (Nilsson et al 1998). The activity of compstatin on the classical and alternative pathway has later been confirmed and further investigated by independent groups from both academic research and pharmaceutical industry (Furlong et al 2000;Klegeris et al 2002).…”

Section: Discovery and Initial Characterizationmentioning

confidence: 86%

“…In contrast to the restriction concerning the ring structure, compstatin was found to be more tolerant to the replacement or modification of the terminal residues (Ile-1, Thr-13), which may be beneficial for improving the stability towards exopeptidases (Furlong et al 2000;. Surprisingly, acetylation of the N-terminus did not only improve the degradation profile (see Chap.…”

Section: Tuning the Structurementioning

confidence: 97%

“…Maintenance of this turn structure seemed to be essential for the functionality of compstatin, since both the linearization as well as the replacement of residues 5-8 by alanine led to a dramatic loss in activity (Morikis et al 1998). Similarly, the introduction of D-amino acids into the compstatin ring in an attempt to reinforce the β-turn conformation led to a complete loss of activity in most cases (Furlong et al 2000). Finally, a cycle size of 11 residues was shown to be mandatory since none of the shorter deletion analogs maintained activity .…”

mentioning

confidence: 99%

“…Similarly, the introduction of D-amino acids into the compstatin ring in an attempt to reinforce the β-turn conformation led to a complete loss of activity in most cases (Furlong et al 2000). Finally, a cycle size of 11 residues was shown to be mandatory since none of the shorter deletion analogs maintained activity .In contrast to the restriction concerning the ring structure, compstatin was found to be more tolerant to the replacement or modification of the terminal residues (Ile-1, Thr-13), which may be beneficial for improving the stability towards exopeptidases (Furlong et al 2000;. Surprisingly, acetylation of the N-terminus did not only improve the degradation profile (see Chap.…”

mentioning

confidence: 99%

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Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

118

166

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Therapeutic modulation of the human complement system is considered a promising approach for treating a number of pathological conditions. Owing to its central position in the cascade, component C3 is a particularly attractive target for complement-specific drugs. Compstatin, a cyclic tridecapeptide, which was originally discovered from phage-display libraries, is a highly potent and selective C3 inhibitor that demonstrated clinical potential in a series of experimental models. A combination of chemical, biophysical, and computational approaches allowed a remarkable optimization of its binding affinity towards C3 and its inhibitory potency. With the recent announcement of clinical trials with a compstatin analog for the treatment of age-related macular degeneration, another important milestone has been reached on its way to a drug. Furthermore, the release of a co-crystal structure of compstatin with C3c allows a detailed insight into the binding mode and paves the way to the rational design of peptides and mimetics with improved activity. Considering the new incentives and the promising pre-clinical results, compstatin seems to be well equipped for the challenges on its way to a clinical therapeutic. Tackling Complement at its CoreTherapeutic intervention in the human complement system has long been recognized as a promising strategy for the treatment of a series of ischemic, inflammatory and autoimmune diseases (Lambris and Holers 2000;Ricklin and Lambris 2007a). In principle, the large network of soluble and cell-surface-bound proteins, which builds the base of the complement cascade, offers a variety of potential drug targets. However, the quest for complement-specific therapeutics proved to be much more challenging than initially anticipated. With the therapeutic antibody eculizumab (Soliris ® , Alexion Pharmaceuticals, Inc.) against paroxysmal nocturnal hemoglobinuria, the first drug with proven complement connectivity has been marketed only recently (Ricklin and Lambris 2007a;Rother et al. 2007). A second complement-associated compound, purified C1 esterase inhibitor (C1-INH), is available as a therapeutic option for the treatment of hereditary angioedema in several countries. However, its mechanism of action may be closer related to the bradykinin-kallikrein than the complement cascade (Davis 2006). Strikingly, both drugs cover relatively rare diseases and have been developed with the aid of orphan drug regulations. Yet, for many of the more common inflammatory or autoimmune conditions there are no complement drugs on the market. Any extension of the current complement-specific therapeutic arsenal is therefore highly desired.Part of the problem in complement-directed drug discovery is the selection of the right target (Ricklin and Lambris 2007a activation is considered to be the most promising approach in many cases. On a molecular level, inhibition at the level of C3, including the C3 convertases, is of particular interest since both the amplification of all initiation pathways and the generatio...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 83%

Section: Discovery and Initial Characterizationmentioning

confidence: 86%

Section: Tuning the Structurementioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

118

166

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Inhibitor of complement, Compstatin, prevents polymer‐mediated Mac‐1 up‐regulation of human neutrophils independent of biomaterial type tested

Schmidt

Haase

Csomor

et al. 2003

J Biomedical Materials Res

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The inflammatory reaction after cell contact with polymer materials is primarily mediated by activated neutrophils and may, in some cases, lead to exhaustion of neutrophil cell function. A direct consequence of this can be impairment of local or even systemic host defense mechanisms, which in turn can result in foreign body infections. Neutrophil activation, as indicated by the up-regulation of the Mac-1 adhesion receptor, is a reliable parameter for estimating the inflammatory risk due to implanted biomaterials. Because at blood contact, biomaterials immediately acquire a material-specific layer of blood proteins on their surface, including fibrinogen, complement, and immunoglobulin G, it is generally believed that after biomaterial contact, neutrophil activation primarily occurs by interaction with this protein layer. In this study, using our recently established polymer bead in vitro assay, we investigated whether complement inhibition alone can reduce biomaterial-mediated neutrophil activation, independent of the type of polymer and, hence, also its surface chemistry. Complement inhibition was achieved by using Compstatin, a recently developed complement inhibitor that binds to the complement component C3 preventing C3 convertase formation. We revealed significantly reduced (p < or = 0.025) Mac-1 receptor expression levels after 45 min of blood contact with the following polymers (without and with Compstatin): 1. polyurethane, 98.3%, 13.6%; 2. polymethylmetacrylate, 88.5%, 11.0%; and poly-D,L-lactide, 71.8%, 8.4%. Although these three polymer types acquire material-specific protein layers because of their different surface chemistry, complement inhibition by Compstatin alone proved to be sufficient to reduce neutrophil activation after surface contact, thus reducing the risk of biomaterial-mediated inflammatory reaction.

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Conformational interconversion in compstatin probed with molecular dynamics simulations

Mallik¹,

Lambris²,

Morikis³

2003

Proteins

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Compstatin is a 13-residue cyclic peptide that has the potential to become a therapeutic agent against unregulated complement activation. In our effort to understand the structural and dynamic characteristics of compstatin that form the basis for rational and combinatorial optimization of structure and activity, we performed 1-ns molecular dynamics (MD) simulations. We used as input in the MD simulations the ensemble of 21 lowest energy NMR structures, the average minimized structure, and a global optimization structure. At the end of the MD simulations we identified five conformations, with populations ranging between 9% and 44%. These conformations are as follows: 1) coil with alphaR-alphaR beta-turn, as was the conformation of the initial ensemble of NMR structures; 2) beta-hairpin with epsilon-alphaR beta-turn; 3) beta-hairpin with alphaR-alphaR beta-turn; 4) beta-hairpin with alphaR-beta beta-turn; and 5) alpha-helical. Conformational switch was possible with small amplitude backbone motions of the order of 0.1-0.4 A and free energy barrier crossing of 2-11 kcal/mol. All of the 21 MD structures corresponding to the NMR ensemble possessed a beta-turn, with 14 structures retaining the alphaR-alphaR beta-turn type, but the average minimized structure and the global optimization structures were converted to alpha-helical conformations. Overall, the MD simulations have aided to gain insight into the conformational space sampled by compstatin and have provided a measure of conformational interconversion. The calculated conformers will be useful as structural and possibly dynamic templates for optimization in the design of compstatin using structure-activity relations (SAR) or dynamics-activity relations (DAR).

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C3 activation is inhibited by analogs of compstatin but not by serine protease inhibitors or peptidyl α-ketoheterocycles

Cited by 34 publications

References 41 publications

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Inhibitor of complement, Compstatin, prevents polymer‐mediated Mac‐1 up‐regulation of human neutrophils independent of biomaterial type tested

Conformational interconversion in compstatin probed with molecular dynamics simulations

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