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

  • To obtain more potent compstatin analogues, an N-methylation scan of the peptide backbone and amino acid substitutions at position 13 was performed.
  • One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 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.
  • Conclusion: 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.
Author and source information

Authors: Qu H, Magotti P, Ricklin D, Wu EL, Kourtzelis I, Wu YQ, Kaznessis YN, Lambris JD.
Reference: Mol Immunol. 2011 Jan;48(4):481-9. doi: 10.1016/j.molimm.2010.10.004. Epub 2010 Nov 9.