Glycine-replaced derivatives of [Pro3,DLeu9]TL, a temporin L analogue: Evaluation of antimicrobial, cytotoxic and hemolytic activities

Eur J Med Chem. 2017 Oct 20:139:750-761. doi: 10.1016/j.ejmech.2017.08.040. Epub 2017 Aug 21.

Abstract

In this study we designed and synthesized a new library of antimicrobial peptides correlated to [Pro3,DLeu9]TL 1, a temporin L derivative devoid of cytolytic effects in vitro, and investigated the correlation between the α-helical content of the compounds and their antibacterial, cytotoxic and hemolytic activities. We systematically replaced Gly in position 10 of reference peptide with several amino acids. Structure-activity relationship studies of these analogues were performed by means of antimicrobial and cytotoxicity assays along with CD spectroscopy analyses. NMR analysis was also accomplished for compound 10. As well, the most promising peptides were additionally evaluated for their activity against some clinical strains isolated from human skin and for their mechanism of action by studying the kinetics of membrane perturbation of some representative microbial strains. We identified novel analogues with interesting properties that make them attractive lead compounds for potential topical applications.

Keywords: Antimicrobial peptides; SAR study; Spectroscopy studies; Temporin L analogues.

MeSH terms

  • Adult
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemical synthesis
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology*
  • Cell Death / drug effects
  • Cell Line
  • Dose-Response Relationship, Drug
  • Erythrocytes / drug effects
  • Fungi / drug effects
  • Glycine / chemistry
  • Glycine / pharmacology*
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Hemolysis / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Proteins / chemical synthesis
  • Proteins / chemistry
  • Proteins / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Proteins
  • temporin
  • Glycine