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.

Immunobiology (2012-07-17)

Hongchang Qu, Daniel Ricklin, Hongjun Bai, Hui Chen, Edimara S Reis, Mateusz Maciejewski, Apostolia Tzekou, Robert A DeAngelis, Ranillo R G Resuello, Florea Lupu, Paul N Barlow, John D Lambris

PMID22795972

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.

MATERIALS

Product Number

Brand

Product Description

EP951031208

Eppendorf^® Deepwell plates, DNA LoBind, 384 wells, white plate, conical bottom, colorless wells, capacity 200 μL, pack of 40 ea (5 bags × 8 plates)

EP022431005

Eppendorf^® DNA LoBind tubes, capacity 0.5 mL, PCR clean, pkg of 250 ea (5 x 50ea)

EP022431021

Eppendorf^® DNA LoBind tubes, capacity 1.5 mL, PCR clean, pkg of 250 ea (5 x 50ea)

EP951032085

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 500 μL, pkg of 40 ea (5 bags × 8 plates)

EP951040601

Eppendorf^® Protein LoBind Microplate 384/V-PP, PCR clean, V-bottom clear wells, white border, pack of 240 ea (10 bags × 24 plates)

EP951032409

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 500 μL, pkg of 120 ea (10 bags × 12 plates)

EP951031607

Eppendorf^® Deepwell plates, DNA LoBind, 384 wells, white plate, conical bottom, colorless wells, capacity 200 μL, pack of 120 ea (10 bags × 12 plates)

EP951032000

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 500 μL, pkg of 40 ea (5 bags × 8 plates)

EP022431048

Eppendorf^® DNA LoBind tubes, capacity 2.0 mL, PCR clean, pkg of 250 ea (5 x 50ea)

EP951032808

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 1000 μL, pkg of 120 ea (10 bags × 12 plates)

EP951032883

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 1000 μL, pkg of 120 ea (10 bags × 12 plates)

EP951033201

Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 1000 μL, pkg of 80 ea (10 bags × 8 plates)

EP951032921

Eppendorf^® Deepwell plates, Protein LoBind, 96 wells, yellow plate, conical bottom, colorless wells, capacity 500 μL, pkg of 20 ea (5 bags × 4 plates)

EP951033308

Eppendorf^® Deepwell plates, Protein LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 500 μL, pkg of 80 ea (10 bags × 8 plates)

EP022431064

Eppendorf^® Protein LoBind tubes, capacity 0.5 mL, PCR clean, pkg of 100 ea (2 x 50ea)

EP022431081

Eppendorf^® Protein LoBind tubes, capacity 1.5 mL, PCR clean, pkg of 100 ea (2 x 50ea)

EP022431102

Eppendorf^® Protein LoBind tubes, capacity 2.0 mL, PCR clean, pkg of 100 ea (2 x 50ea)

EP951032123

Eppendorf^® Deepwell plates, Protein LoBind, 96 wells, yellow plate, conical bottom, colorless wells, capacity 500 μL, pkg of 40 ea (5 bags × 8 plates)