期刊
MOLECULAR IMMUNOLOGY
卷 48, 期 4, 页码 481-489出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2010.10.004
关键词
Compstatin; N-methylation; Complement inhibitor; Peptide therapeutic; Isothermal titration calorimetry; Surface plasmon resonance
资金
- National Institutes of Health [GM-069736, GM-62134, AI-30040, EB003968, CA112162, AI-068730]
- NATIONAL CANCER INSTITUTE [R01CA112162] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI030040, N01AI030040, P01AI068730] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB003968] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM062134, R24GM069736] Funding Source: NIH RePORTER
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-NH2) displayed a 1000-fold increase in both potency (IC50 = 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. (C) 2010 Elsevier Ltd. All rights reserved.
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