Development of helix-stabilized antimicrobial peptides composed of lysine and hydrophobic α,α-disubstituted α-amino acid residues

Bioorg Med Chem Lett. 2017 Sep 1;27(17):3950-3953. doi: 10.1016/j.bmcl.2017.07.074. Epub 2017 Jul 29.

Abstract

Lysine-based amphipathic nonapeptides, including homochiral peptides [Ac-(l-Lys-l-Lys-Xaa)3-NH2 (Xaa=Gly, Ala, Aib, Ac5c, or Ac6c) and Ac-(d-Lys-d-Lys-Aib)3-NH2], a heterochiral peptide [Ac-(l-Lys-d-Lys-Aib)3-NH2], and a racemic mixture of diastereomeric peptides [Ac-(rac-Lys-rac-Lys-Aib)3-NH2] were designed and synthesized to investigate the relationship between their preferred secondary structures and their antimicrobial activity. Peptide 5, [Ac-(l-Lys-l-Lys-Ac6c)3-NH2] formed a stable α-helical structure and exhibited strong activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa).

Keywords: Antimicrobial activity; Circular dichroism; Helical peptide; α,α-Disubstituted α-amino acid.

MeSH terms

  • Amino Acids / chemistry
  • Amino Acids / pharmacology*
  • Antimicrobial Cationic Peptides / chemical synthesis
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology*
  • Dose-Response Relationship, Drug
  • Escherichia coli / drug effects*
  • Lysine / chemistry
  • Lysine / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Pseudomonas aeruginosa / drug effects*
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Antimicrobial Cationic Peptides
  • Lysine