3 research outputs found
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New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.
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
Recommended from our members
New Compstatin Peptides Containing N‑Terminal Extensions and Non-Natural Amino Acids Exhibit Potent Complement Inhibition and Improved Solubility Characteristics
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-ICVWQDWÂGAHRCT-NH<sub>2</sub>, 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