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Comparison of Biophysical and Biologic Properties of α ‐Helical Enantiomeric Antimicrobial Peptides
Author(s) -
Chen Yuxin,
Vasil Adriana I.,
Rehaume Linda,
Mant Colin T.,
Burns Jane L.,
Vasil Michael L.,
Hancock Robert E. W.,
Hodges Robert S.
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2006.00349.x
Subject(s) - peptide , enantiomer , antimicrobial peptides , circular dichroism , antimicrobial , chemistry , trypsin , bacteria , biochemistry , candida albicans , stereochemistry , gram negative bacteria , microbiology and biotechnology , enzyme , biology , escherichia coli , organic chemistry , gene , genetics
In our previous study (Chen et al. J Biol Chem 2005, 280:12316–12329), we utilized an α ‐helical antimicrobial peptide V 681 as the framework to study the effects of peptide hydrophobicity, amphipathicity, and helicity on biologic activities where we obtained several V 681 analogs with dramatic improvement in peptide therapeutic indices against gram‐negative and gram‐positive bacteria. In the present study, the d ‐enantiomers of three peptides – V 681 , V13A D and V13K L were synthesized to compare biophysical and biologic properties with their enantiomeric isomers. Each d ‐enantiomer was shown by circular dichroism spectroscopy to be a mirror image of the corresponding l ‐isomer in benign conditions and in the presence of 50% trifluoroethanol. l ‐ and d ‐enantiomers exhibited equivalent antimicrobial activities against a diverse group of Pseudomonas aeruginosa clinical isolates, various gram‐negative and gram‐positive bacteria and a fungus. In addition, l ‐ and d ‐enantiomeric peptides were equally active in their ability to lyse human red blood cells. The similar activity of l ‐ and d ‐enantiomeric peptides on prokaryotic or eukaryotic cell membranes suggests that there are no chiral receptors and the cell membrane is the sole target for these peptides. Peptide d ‐V13K D showed significant improvements in the therapeutic indices compared with the parent peptide V 681 by 53‐fold against P. aeruginosa strains, 80‐fold against gram‐negative bacteria, 69‐fold against gram‐positive bacteria, and 33‐fold against Candida albicans . The excellent stability of d ‐enantiomers to trypsin digestion (no proteolysis by trypsin) compared with the rapid breakdown of the l ‐enantiomers highlights the advantage of the d ‐enantiomers and their potential as clinical therapeutics.