New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.
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abstract
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 -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.
Gorham, R. D., Forest, D. L., Khoury, G. A., Smadbeck, J., Beecher, C. N., Healy, E. D., ... Morikis, D.
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Gorham, Ronald D||Forest, David L||Khoury, George A||Smadbeck, James||Beecher, Consuelo N||Healy, Evangeline D||Tamamis, Phanourios||Archontis, Georgios||Larive, Cynthia K||Floudas, Christodoulos A||Radeke, Monte J||Johnson, Lincoln V||Morikis, Dimitrios
