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  • Title: Structure/function studies of an endotoxin-neutralizing peptide derived from bactericidal/permeability-increasing protein.
    Author: Wasiluk KR, Leslie DB, Vietzen PS, Mayo KH, Dunn DL.
    Journal: Surgery; 2004 Aug; 136(2):253-60. PubMed ID: 15300188.
    Abstract:
    BACKGROUND: Bactericidal/permeability-increasing protein, BPI, has a beta-turn with alternating cationic and hydrophobic residues in its lipopolysaccharide (endotoxin, LPS)-binding domain. A peptide, betapep25, was designed with 9 residues of the LPS-binding domain of BPI flanked by beta-turn-inducing elements. Thereafter, we sought to use single amino acid substitutions to identify residues that are important for the biological activities of betapep25. METHODS: Single alanine or norleucine replacement "walkthrough" peptides based on betapep25 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 beta-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 betapep25. 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.
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