A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic a-helical antimicrobial peptide A12L/A20L （Ac-KWKSFLKTF...A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic a-helical antimicrobial peptide A12L/A20L （Ac-KWKSFLKTFKSLK KTVLHTLLKAISS-amide） was used as the framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activi- ties of o-helical antimicrobial peptides. Peptide helicity was measured by circular dichroism spectroscopy and demonstrated to correlate with the hydrophobicity of peptides and the numbers of D-amino acid substitu- tions. Therapeutic index was used to evaluate the selectivity of peptides against prokaryotic cells. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, the hemolytic activity of peptide analogs have been significantly reduced. Compared to the parent peptide, the therapeutic indices were improved of 44-fold and 22-fold against Gram-negative and Gram- positive bacteria, respectively. In addition, D- and L-diastereomeric peptides exhibited lower interaction with zwitterionic eukaryotic membrane and showed the significant membrane damaging effect to bacterial cells. Helicity was proved to play a crucial role on peptide specificity and biological activities. By simply replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial pep- tides with enhanced specificity.展开更多
基金This work was supported by the National Natural Science Founda- tion of China （Grant Nos. 81373445 to Y. X. C. and 81272471 to H. Y. J.）, the Innovative Team of Peptide Drugs of Jilin Province （No. 20121807, Y. X. C.）, the Natural Science Foundation of Jilin Prov- ince （No. 20140101042JC, Y. B. H.）, and a Basic Scientific Research Grants from Jilin University （Y. X. C. and Y. B. H）.
文摘A major barrier to the use of antimicrobial peptides as antibiotics is the toxicity or ability to lyse eukaryotic cells. In this study, a 26-residue amphipathic a-helical antimicrobial peptide A12L/A20L （Ac-KWKSFLKTFKSLK KTVLHTLLKAISS-amide） was used as the framework to design a series of D- and L-diastereomeric peptides and study the relationships of helicity and biological activi- ties of o-helical antimicrobial peptides. Peptide helicity was measured by circular dichroism spectroscopy and demonstrated to correlate with the hydrophobicity of peptides and the numbers of D-amino acid substitu- tions. Therapeutic index was used to evaluate the selectivity of peptides against prokaryotic cells. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, the hemolytic activity of peptide analogs have been significantly reduced. Compared to the parent peptide, the therapeutic indices were improved of 44-fold and 22-fold against Gram-negative and Gram- positive bacteria, respectively. In addition, D- and L-diastereomeric peptides exhibited lower interaction with zwitterionic eukaryotic membrane and showed the significant membrane damaging effect to bacterial cells. Helicity was proved to play a crucial role on peptide specificity and biological activities. By simply replacing the hydrophobic or the hydrophilic amino acid residues on the non-polar or the polar face of these amphipathic derivatives of the parent peptide with D-amino acids, we demonstrated that this method could have excellent potential for the rational design of antimicrobial pep- tides with enhanced specificity.
