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

Highlights:

• 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.