Abstract
A truncated version of host defense peptide chicken cathelicidin-2, C1-15, possesses potent, broad
spectrum antibacterial activity. A variant of this peptide, F2,5,12W, which contains 3 phenylalanine to
tryptophan substitutions, possesses improved antibacterial activity and lipopolysaccharide (LPS) neutralizing
activity compared to C1-15. In order to improve the proteolytic resistance of both peptides we
engineered novel chicken cathelicidin-2 analogs by substitution of l- with d-amino acids and head-to-tail
cyclization. Both cyclic and d-amino acid variants showed enhanced stability in human serum compared
to C1-15 and F2,5,12W. The d-amino acid variants were fully resistant to proteolysis by trypsin and bacterial
proteases. Head-to-tail cyclization of peptide F2,5,12Wresulted in a 3.5-fold lower cytotoxicity toward
peripheral blood mononuclear cells. In general, these modifications did not influence antibacterial and LPS
neutralization activities. It is concluded that for the development of novel therapeutic compounds based
on chicken cathelicidin-2 d-amino acid substitutions and cyclization must be considered. These modifications
increase the stability and lower cytotoxicity of the peptides without altering their antimicrobial
potency.
spectrum antibacterial activity. A variant of this peptide, F2,5,12W, which contains 3 phenylalanine to
tryptophan substitutions, possesses improved antibacterial activity and lipopolysaccharide (LPS) neutralizing
activity compared to C1-15. In order to improve the proteolytic resistance of both peptides we
engineered novel chicken cathelicidin-2 analogs by substitution of l- with d-amino acids and head-to-tail
cyclization. Both cyclic and d-amino acid variants showed enhanced stability in human serum compared
to C1-15 and F2,5,12W. The d-amino acid variants were fully resistant to proteolysis by trypsin and bacterial
proteases. Head-to-tail cyclization of peptide F2,5,12Wresulted in a 3.5-fold lower cytotoxicity toward
peripheral blood mononuclear cells. In general, these modifications did not influence antibacterial and LPS
neutralization activities. It is concluded that for the development of novel therapeutic compounds based
on chicken cathelicidin-2 d-amino acid substitutions and cyclization must be considered. These modifications
increase the stability and lower cytotoxicity of the peptides without altering their antimicrobial
potency.
| Original language | English |
|---|---|
| Pages (from-to) | 875-880 |
| Number of pages | 6 |
| Journal | Peptides |
| Volume | 32 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2011 |
Keywords
- Host defense peptide
- Chicken cathelicidin-2
- Stability
- d-Amino acid substitution
- Cyclization