Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency.
Compstatin is a 13-residue disulfide-bridged peptide that inhibits a key step in the activation of the human complement system. Compstatin and its derivatives have shown great promise for the treatment of many clinical disorders associated with unbalanced complement activity. To obtain more potent compstatin analogues, we have now performed an N-methylation scan of the peptide backbone and amino acid substitutions at position 13. One analogue (Ac-I[CVW(Me)QDW-Sar-AHRC](NMe)I-NH(2)) displayed a 1000-fold increase in both potency (IC(50) = 62 nM) and binding affinity for C3b (K(D) = 2.3 nM) over that of the original compstatin. Biophysical analysis using surface plasmon resonance and isothermal titration calorimetry suggests that the improved binding originates from more favorable free conformation and stronger hydrophobic interactions. This study provides a series of significantly improved drug leads for therapeutic applications in complement-related diseases, and offers new insights into the structure-activity relationships of compstatin analogues.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hongchang
H
Qu
Paola
P
Magotti
Daniel
D
Ricklin
Emilia L
EL
Wu
Ioannis
I
Kourtzelis
You-Qiang
YQ
Wu
Yiannis N
YN
Kaznessis
John D
JD
Lambris
D000595:Amino Acid Sequence; D003167:Complement Activation / Q000187:drug effects; D003169:Complement Inactivator Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013816:Thermodynamics
D003169:Complement Inactivator Proteins; D010456:Peptides, Cyclic; C111828:compstatin