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

Abstract

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.

Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria

“…Over the past decade, optimization studies have been conducted to develop compstatin derivatives with improved characteristics for systemic use. [17][18][19] The current lead analog Cp40 (clinically developed by Amyndas Pharmaceuticals) 13 shows strong binding affinity for C3b (K D ;0.5 nM) and a plasma half-life (t 1/2 ;12 hours) that exceeds typical peptide drugs.18 Despite these favorable properties, it is anticipated that a long-acting derivative of Cp40 based on sitespecific addition of polyethylene glycol (PEG) moieties may benefit a sustained pharmacologic complement inhibition as needed in PNH.By investigating the efficacy of Cp40 and its long-acting PEGylated derivatives regarding the protection of PNH erythrocytes in vitro and evaluating their pharmacokinetic properties in NHP, we describe a novel potential treatment option for PNH. …”

Monospecific Inhibitors Show That Both Mannan-binding Lectin-associated Serine Protease-1 (MASP-1) and -2 Are Essential for Lectin Pathway Activation and Reveal Structural Plasticity of MASP-2

“…Phage display was used to generate compstatin, a powerful peptide inhibitor that binds to C3 and inhibits the common central step of the complement cascade (58). Another phage display-selected inhibitor is complin, which targets factor B and C2 and consequently inhibits all the three pathways (59).…”

Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model

“…The samples were incubated for 2, 4 or 6 h at 37°C in a heat cabinet under continuous, slow rotation around the vertical axis using a Rock'n Roller (Labinco B.V., Breda, the Netherlands). In the experiments with the complement inhibitors, blood was 20 ), C5 inhibitor Soliris ® (eculizumab; Alexion Pharmaceuticals, Zürich, Switzerland; final concentration 100 µg/mL), C5a receptor antagonist (C5aRA) PMX53 (final concentration 10 µg/mL; as previously described 21 ) or C3a receptor antagonist (C3aRA; final concentration 50 µM; kindly provided by Robert S Ames) or PBS in the ratio blood to inhibitor or PBS equal to 5:1. IONPs and controls were then added to the pre-incubated blood and further incubated for various time periods.…”