Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 2, Pages 814-826Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501345y
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Funding
- Carolyn K. McGillvray Memorial Award for Macular Degeneration Research
- Garland Initiative for Vision at University of California, Santa Barbara
- BrightFocus Foundation [M2013106]
- National Institutes of Health [R01GM052032]
- National Science Foundation [DGE-1148900]
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Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with a-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.
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