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

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 rel

SUBMITTER: Qu H 

PROVIDER: S-EPMC3518557 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature