New analogs of the clinical complement inhibitor compstatin with with subnanomolar affinity and enhanced pharmacokinetic properties

  • This study reports improvements in both the inhibitory potency and pharmacokinetic parameters of compstatin that broaden its clinical applications.
  • Selective modification of the compstatin N-terminus with non-proteinogenic amino acids resulted in the first analogue with subnanomolar binding affinity (KD=0.5nM) and other similarly potent derivatives with improved solubility in clinically relevant solvents.
  • Detailed structure-activity relationship studies based on biophysical and computational methods revealed key structural determinants for the observed improvements.
  • Importantly, pharmacokinetic evaluation in non-human primates revealed target-driven elimination kinetics with plasma half-life values exceeding expectations for peptidic drugs (close to 12h).
  • Conclusion: This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.
Author and source information

Authors: Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, Tzekou A, DeAngelis RA, Resuello RR, Lupu F, Barlow PN, Lambris JD.
Reference: Immunobiology. 2013 Apr;218(4):496-505. doi: 10.1016/j.imbio.2012.06.003. Epub 2012 Jun 17.