Conformational analysis of compstatin analogues with molecular dynamics simulations in explicit water

Tamamis, Phanourios; Skourtis, Spiros S.; Morikis, Dimitrios; Lambris, John D.; Archontis, Georgios

doi:10.1016/j.jmgm.2007.03.014

Cited by 12 publications

(19 citation statements)

References 41 publications

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“…Previous studies have shown that the bound conformation of [Trp 4 ]-Ac-compstatin as observed in the crystal structure is clearly distinct from its free solution conformation obtained from computational and NMR studies (Janssen et al, 2007; Mallik et al, 2005; Mulakala et al, 2007; Tamamis et al, 2007). The large conformational rearrangements required for tight binding to its site in C3 and the accompanying loss of flexibility of the ring structure might therefore both contribute to the entropic penalty (Janssen et al, 2007; Killian et al, 2009).…”

Section: Discussionmentioning

confidence: 72%

“…Analysis of a variety of compstatin analogues including [Trp 4 ]-Ac-compstatin using molecular dynamics (MD) simulations and NMR revealed a highly flexible ring structure that features a β-turn comprising residues Gln 5 -Asp 6 -Trp 7 -Gly 8 in solution (Mallik et al, 2005; Mallik et al, 2003; Morikis et al, 1998; Tamamis et al, 2007). Although this turn was considered an important structural feature, it was later found that the intrinsic tendency of a compstatin analogue to form a β-turn does not strictly correlate with its inhibitory potency (Morikis et al, 2002; Tamamis et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Although this turn was considered an important structural feature, it was later found that the intrinsic tendency of a compstatin analogue to form a β-turn does not strictly correlate with its inhibitory potency (Morikis et al, 2002; Tamamis et al, 2007). Even more importantly, the C3c-bound structure of [Trp 4 ]-Ac-compstatin revealed that the position of β-turn had shifted considerably from positions 5–8 to 8–11, suggesting a large conformational change that might contribute to the large entropic penalty found for this analogue (−TΔS = 8.8 kcal/mol) (Janssen et al, 2007; Katragadda et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Magotti

Ricklin

et al. 2011

Molecular Immunology

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Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH2) displayed a 1,000-fold increase in both potency (IC50=62 nM) and binding affinity for C3b (KD=2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Magotti

Ricklin

et al. 2011

Molecular Immunology

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“…Leveraging data from our recent (Bellows et al, 2010a; Tamamis et al, 2010; López de Victoria et al, 2011; Tamamis et al, 2012) and other studies of compstatin family peptides (Sahu et al, 1996; Morikis et al, 1998; Furlong et al, 2000; Sahu et al, 2000; Morikis and Lambris, 2002; Morikis et al, 2002; Klepeis et al, 2003; Soulika et al, 2003; Klepeis et al, 2004; Morikis et al, 2004; Mallik et al, 2005; Morikis et al, 2005; Morikis and Lambris, 2005; Katragadda et al, 2006; Janssen et al, 2007; Ricklin and Lambris, 2008; Magotti et al, 2009; Qu et al, 2009), including MD simulation studies based on the structure of free (Mallik et al, 2003; Mallik et al, 2005; Mallik and Morikis, 2005; Song et al, 2005; Tamamis et al, 2007) and C3c-bound compstatin (Tamamis et al, 2010; Tamamis et al, 2011; Tamamis et al, 2012), we furthered the optimization of compstatin analogs using MD simulations. Our goal in this work is to increase the polarity/hydrophobicity ratio in the peptide sequence without compromising the essential hydrophobic contacts with C3.…”

Section: Introductionmentioning

confidence: 97%

Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures

Gorham

Forest

Tamamis

et al. 2013

Experimental Eye Research

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We have used a novel human retinal pigmented epithelial (RPE) cell-based model that mimics drusen biogenesis and the pathobiology of age-related macular degeneration to evaluate the efficacy of newly designed peptide inhibitors of the complement system. The peptides belong to the compstatin family and, compared to existing compstatin analogs, have been optimized to promote binding to their target, complement protein C3, and to enhance solubility by improving their polarity/hydrophobicity ratios. Based on analysis of molecular dynamics simulation data of peptide-C3 complexes, novel binding features were designed by introducing intermolecular salt bridge-forming arginines at the N-terminus and at position -1 of N-terminal dipeptide extensions. Our study demonstrates that the RPE cell assay has discriminatory capability for measuring the efficacy and potency of inhibitory peptides in a macular disease environment.

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“…4). The arsenal of active and inactive analogs in combination with the known solution structures led to the development of sophisticated in silico models based on QSAR, molecular dynamics, or conformational space annealing (Mallik et al 2003;Mulakala et al 2007;Song et al 2005;Tamamis et al 2007). However, the most important breakthrough was reached with the release of the first co-crystal structure between a compstatin analog and C3c (see Chap.…”

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confidence: 99%

Compstatin: A Complement Inhibitor on its Way to Clinical Application

Ricklin

Lambris²

2008

Advances in Experimental Medicine and Biology

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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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Conformational analysis of compstatin analogues with molecular dynamics simulations in explicit water

Cited by 12 publications

References 41 publications

Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency

Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures

Compstatin: A Complement Inhibitor on its Way to Clinical Application

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