High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs

Sci Rep. 2015 Nov 4;5:15963. doi: 10.1038/srep15963.

Abstract

We used a template-assisted approach to develop synthetic antimicrobial peptides, which differ from naturally occurring antimicrobial peptides that can compromise host natural defenses. Previous researches have demonstrated that symmetrical distribution patterns of amino acids contribute to the antimicrobial activity of natural peptides. However, there is little research describing such design ideas for synthetic α-helical peptides. Therefore, here, we established a centrosymmetric α-helical sequence template (y + hhh + y)n (h, hydrophobic amino acid; +, cationic amino acid; y, Gly or hydrophobic amino acid), which contributed to amphipathicity, and a series of centrosymmetric peptides was designed with pairs of small amino acids (Ala and Gly), which were utilized to modulate the biological activity. The centrosymmetric peptides with 3 repeat units exhibited strong antimicrobial activity; in particular, the Gly-rich centrosymmetric peptide GG3 showed stronger selectivity for gram-negative bacteria without hemolysis. Furthermore, beyond our expectation, fluorescence spectroscopy and electron microscopy analyses indicated that the GG3, which possessed poor α-helix conformation, dramatically exhibited marked membrane destruction via inducing bacterial membrane permeabilization, pore formation and disruption, even bound DNA to further exert antimicrobial activity. Collectively, the Gly-rich centrosymmetric peptide GG3 was an ideal candidate for commercialization as a clinical therapeutic to treat gram-negative bacterial infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemical synthesis
  • Antimicrobial Cationic Peptides / pharmacology*
  • Cell Membrane / drug effects
  • Cell Membrane Permeability / drug effects*
  • Drug Design
  • Drug Synergism
  • Fluorescence Resonance Energy Transfer
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacterial Infections / drug therapy*
  • Hydrophobic and Hydrophilic Interactions
  • Microbial Sensitivity Tests
  • Oligopeptides / chemical synthesis
  • Oligopeptides / pharmacology*
  • Protein Structure, Secondary

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Oligopeptides
  • glycyl-glycyl-glycine