Effects of single D-amino acid substitutions on disruption of β-sheet structure and hydrophobicity in cyclic 14-residue antimicrobial peptide analogs related to gramicidin S

被引:82
作者
Lee, DL
Powers, JPS
Pflegerl, K
Vasil, ML
Hancock, REW
Hodges, RS
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Biochem & Mol Genet, Denver, CO 80262 USA
[2] Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada
[3] Univ British Columbia, Dept Microbiol, Vancouver, BC V6T 1ZJ, Canada
[4] Univ Agr Sci, Inst Appl Microbiol, A-1190 Vienna, Austria
[5] Univ Colorado, Hlth Sci Ctr, Dept Microbiol, Denver, CO 80262 USA
来源
JOURNAL OF PEPTIDE RESEARCH | 2004年 / 63卷 / 02期
关键词
D-amino acids; antimicrobial peptides; cationic peptides; cyclic peptides; gramicidin S; peptide diastereomers; beta-sheet; structure-activity relationship;
D O I
10.1046/j.1399-3011.2003.00106.x
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Gramicidin 5 (GS) is a 10-residue cyclic beta-sheet peptide with lytic activity against the membranes of both microbial and human cells, i.e. it possesses little to no biologic specificity for either cell type. Structure-activity studies of de novo-designed 14-residue cyclic peptides based on GS have previously shown that higher specificity against microbial membranes, i.e. a high therapeutic index (TI), can be achieved by the replacement of a single L-amino acid with its corresponding D-enantiomer [Kondejewski, L.H. et al. (1999) J. Biol. Chem. 274, 13181]. The diastereomer with a D-Lys substituted at position 4 caused the greatest improvement in specificity vs. other L to D substitutions within the cyclic 14-residue peptide GS14, through a combination of decreased peptide amphipathicity and disrupted P-sheet structure in aqueous conditions [McInnes, C. et al. (2000) J. Biol. Chem. 275, 14287]. Based on this information, we have created a series of peptide diastereomers substituted only at position 4 by a D- or L-amino acid (Leu, Phe, Tyr, Asn, Lys, and achiral Gly). The amino acids chosen in this study represent a range of hydrophobicities/hydrophilicities as a subset of the 20 naturally occurring amino acids. While the D- and L-Substitutions of Leu, Phe, and Tyr all resulted in strong hemolytic activity, the substitutions of hydrophilic D-amino acids D-Lys and D-Asn in GS14 at position 4 resulted in weaker hemolytic activity than in the L-diastereomers, which demonstrated strong hemolysis. All of the L-Substitutions also resulted in poor antimicrobial activity and an extremely low TI, while the antimicrobial activity of the D-substituted peptides tended to improve based on the hydrophilicity of the residue. D-Lys was the most polar and most efficacious substitution, resulting in the highest TI. Interestingly, the hydrophobic D-amino acid substitutions had superior antimicrobial activity vs. the L-enantiomers although substitution of a hydrophobic D-amino acid increases the nonpolar face hydrophobicity. These results further support the role of hydrophobicity of the nonpolar face a major influence on microbial specificity, but also highlights the importance of a disrupted P-sheet structure on antimicrobial activity.
引用
收藏
页码:69 / 84
页数:16
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