Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency
| Autor: | Hongchang Qu, Daniel Ricklin, Emilia L. Wu, Ioannis Kourtzelis, You-Qiang Wu, John D. Lambris, Paola Magotti, Yiannis N. Kaznessis |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
chemistry.chemical_classification
Complement Inactivator Proteins Stereochemistry Molecular Sequence Data Immunology Peptide Isothermal titration calorimetry Plasma protein binding Peptides Cyclic Article Amino acid Complement system Kinetics Complement inhibitor chemistry Biochemistry Humans Thermodynamics Amino Acid Sequence Complement Activation Molecular Biology Peptide sequence Protein Binding |
| Zdroj: | Molecular Immunology. 48:481-489 |
| ISSN: | 0161-5890 |
| DOI: | 10.1016/j.molimm.2010.10.004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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