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

Highlights:

• 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.