Improved proteolytic stability of chicken cathelicidin-2 derived peptides by d-amino acid substitutions and cyclization
| Jazyk: | angličtina |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Amino acid substitution
Unclassified drug Phenylalanine Cytotoxicity Protein variant Cathelicidin 2 Proteinase Bactericidal activity Protein degradation Article EELS - Earth Bacterial protein Bacterium lipopolysaccharide Life Protein stability Bacteria (microorganisms) Priority journal Tryptophan CBRN - CBRN Protection Chicken cathelicidin-2 Cathelicidin Peripheral blood mononuclear cell Nonhuman Environmental and Life Sciences Protein modification Peptide synthesis Human cell Cyclization d-Amino acid substitution Host defense peptide Antibacterial activity Protein engineering Stability Controlled study Human |
| Popis: | 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 F2,5,12W resulted 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. © 2011 Elsevier Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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