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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gorham RD Jr,Forest DL,Khoury GA,Smadbeck J,Beecher CN,Healy ED,Tamamis P,Archontis G,Larive CK,Floudas CA,Radeke MJ,Johnson LV,Morikis Ddoi
10.1021/jm501345ysubject
Has Abstractpub_date
2015-01-22 00:00:00pages
814-26issue
2eissn
0022-2623issn
1520-4804journal_volume
58pub_type
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