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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 α-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.|
|Citation:||Gorham Jr, Ronald D., David L. Forest, George A. Khoury, James Smadbeck, Consuelo N. Beecher, Evangeline D. Healy, Phanourios Tamamis, Georgios Archontis, Cynthia K. Larive, Christodoulos A. Floudas, Monte J. Radeke, Lincoln V. Johnson, and Dimitrios Morikis. "New Compstatin Peptides Containing N-Terminal Extensions and Non-Natural Amino Acids Exhibit Potent Complement Inhibition and Improved Solubility Characteristics." Journal of Medicinal Chemistry 58, no. 2 (2015): 814-826. doi: 10.1021/jm501345y|
|Pages:||814 - 826|
|Type of Material:||Journal Article|
|Journal/Proceeding Title:||Journal of Medicinal Chemistry|
|Version:||Final published version. This is an open access article.|
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