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

New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Qu, H., Ricklin, D., Bai, H., Chen, H., Reis, S, E., Maciejewski, M., Tzekou, A., DeAngelis, A, R., Resuello, G, R. R, Lupu, F., Barlow, N, P., Lambris, & D, J. Immunobiology, 218(4):496--505, April, 2013.

Paper doi abstract bibtex

Therapeutic modulation of the complement system has become increasingly important in line with the growing recognition of the role of complement in numerous diseases. Compstatin, a peptidic inhibitor that acts at the central level of the complement cascade, is currently in clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report 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). This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.

@article{ Qu2013,
  abstract = {Therapeutic modulation of the complement system has become increasingly important in line with the growing recognition of the role of complement in numerous diseases. Compstatin, a peptidic inhibitor that acts at the central level of the complement cascade, is currently in clinical evaluation but routes to improve its efficacy have not yet been fully explored. Here, we report 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). This successful optimization strategy is expected to pave the way for systemic administration of compstatin in a range of clinical conditions.},
  author = {Qu, Hongchang and Ricklin, Daniel and Bai, Hongjun and Chen, Hui and Reis, Edimara S and Maciejewski, Mateusz and Tzekou, Apostolia and DeAngelis, Robert A and Resuello, Ranillo R G and Lupu, Florea and Barlow, Paul N and Lambris, John D},
  doi = {10.1016/j.imbio.2012.06.003},
  issn = {1878-3279},
  journal = {Immunobiology},
  month = {April},
  number = {4},
  pages = {496--505},
  pmid = {22795972},
  title = {{New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties.}},
  url = {http://www.ncbi.nlm.nih.gov/pubmed/22795972},
  volume = {218},
  year = {2013}
}

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Here, we report 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). 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