Antimicrobial peptides(AMPs),with their extraordinary properties,such as broad-spectrum activity,rapid action and difficult development of resistance,have become promising molecules as new antibiotics.Despite their va...Antimicrobial peptides(AMPs),with their extraordinary properties,such as broad-spectrum activity,rapid action and difficult development of resistance,have become promising molecules as new antibiotics.Despite their various mechanisms of action,the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action.Moreover,it is generally accepted that the membrane is the primary target of most AMPs,and the interaction between AMPs and eukaryotic cell membranes(causing toxicity to host cells)limits their clinical application.Therefore,researchers are engaged in reforming or de novo designing AMPs as a‘singleedged sword’that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells.To improve the antimicrobial activity of AMPs,the relationship between the structure and function of AMPs has been rigorously pursued.In this review,we focus on the current knowledge of α-helical cationic antimicrobial peptides,one of the most common types of AMPs in nature.展开更多
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 Natural Science Foundation of China Grant No.30840029Grants for Doctorate Program of New Teacher,Ministry of Education of China,No.20070183062,No.200801831064the Excellent Youth Program of the Jilin Provincial Science&Technology Department,China,Grant No.20070111.
文摘Antimicrobial peptides(AMPs),with their extraordinary properties,such as broad-spectrum activity,rapid action and difficult development of resistance,have become promising molecules as new antibiotics.Despite their various mechanisms of action,the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action.Moreover,it is generally accepted that the membrane is the primary target of most AMPs,and the interaction between AMPs and eukaryotic cell membranes(causing toxicity to host cells)limits their clinical application.Therefore,researchers are engaged in reforming or de novo designing AMPs as a‘singleedged sword’that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells.To improve the antimicrobial activity of AMPs,the relationship between the structure and function of AMPs has been rigorously pursued.In this review,we focus on the current knowledge of α-helical cationic antimicrobial peptides,one of the most common types of AMPs in nature.
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.
