Title
Improved proteolytic stability of chicken cathelicidin-2 derived peptides by d-amino acid substitutions and cyclization
Author
Molhoek, E.M.
van Dijk, A.
Veldhuizen, E.J.A.
Haagsman, H.P.
Bikker, F.J.
Publication year
2011
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 F2,5,12W 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.
Subject
Life
CBRN - CBRN Protection
EELS - Earth, Environmental and Life Sciences
Chicken cathelicidin-2
Cyclization
d-Amino acid substitution
Host defense peptide
Stability
Bacterial protein
Bacterium lipopolysaccharide
Cathelicidin
Cathelicidin 2
Phenylalanine
Proteinase
Tryptophan
Unclassified drug
Amino acid substitution
Antibacterial activity
Article
Bactericidal activity
Controlled study
Cyclization
Cytotoxicity
Human
Human cell
Nonhuman
Peptide synthesis
Peripheral blood mononuclear cell
Priority journal
Protein degradation
Protein engineering
Protein modification
Protein stability
Protein variant
Bacteria (microorganisms)
To reference this document use:
http://resolver.tudelft.nl/uuid:940ebb82-f53c-48b9-9404-437276810ed9
DOI
https://doi.org/10.1016/j.peptides.2011.02.017
TNO identifier
429737
ISSN
0196-9781
Source
Peptides, 32 (5), 875-880
Document type
article