Structure/function studies of an endotoxin-neutralizing peptide derived from bactericidal/permeability-increasing protein

Karen R. Wasiluk, Daniel B Leslie, Paul S. Vietzen, Kevin H Mayo, David L. Dunn

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Background Bactericidal/permeability-increasing protein, BPI, has a β-turn with alternating cationic and hydrophobic residues in its lipopolysaccharide (endotoxin, LPS)-binding domain. A peptide, βpep25, was designed with 9 residues of the LPS-binding domain of BPI flanked by β-turn-inducing elements. Thereafter, we sought to use single amino acid substitutions to identify residues that are important for the biological activities of βpep25. Methods Single alanine or norleucine replacement "walkthrough" peptides based on βpep25 were generated and tested for their ability to kill P aeruginosa and to neutralize endotoxin. Results Substitution of all lysines inhibited bactericidal activity. Inhibition of LPS-neutralizing activity was seen in 9 peptides in which an alanine or norleucine was substituted for each of 4 of the basic residues and 1 hydrophobic residue from the LPS-binding region of BPI and 4 hydrophobic residues from the β-turn-inducing regions flanking the LPS-binding region on the carboxy-terminal side. Intriguingly, these last 4 substitutions resulted in peptides that exhibited increased bactericidal activity compared to βpep25. Conclusions These results demonstrate the importance of both cationic and hydrophobic amino acid residues to bactericidal and endotoxin-neutralizing activities. These perturbations of biological activity should be considered in the design of synthetic peptide endotoxin antagonists.

Original languageEnglish (US)
Pages (from-to)253-260
Number of pages8
Issue number2
StatePublished - Aug 2004

Bibliographical note

Funding Information:
Supported by National Institutes of Health grant RO1 GM 32414.

Copyright 2012 Elsevier B.V., All rights reserved.


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