Comparison of biophysical and biologic properties of α-helical enantiomeric antimicrobial peptides

被引:106
作者
Chen, YX
Vasil, AI
Rehaume, L
Mant, CT
Burns, JL
Vasil, ML
Hancock, REW
Hodges, RS
机构
[1] Univ Colorado, Dept Biochem & Mol Genet, Aurora, CO 80045 USA
[2] Hlth Sci Ctr, Aurora, CO 80045 USA
[3] Univ Colorado, Dept Microbiol, Aurora, CO 80045 USA
[4] Univ British Columbia, Dept Microbiol, Vancouver, BC V6T 1Z3, Canada
[5] Univ Washington, Childrens Hosp & Reg Med Ctr, Infect Dis Sect, Seattle, WA 98109 USA
关键词
alpha-helical peptides; antimicrobial activity; antimicrobial peptides; enantiomers; hemolytic activity; mechanism;
D O I
10.1111/j.1747-0285.2006.00349.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In our previous study (Chen et al. J Biol Chem 2005, 280:12316-12329), we utilized an alpha-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.
引用
收藏
页码:162 / 173
页数:12
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