A cell-penetrant lactam-stapled peptide for targeting eIF4E protein-protein interactions

Eur J Med Chem. 2020 Nov 1:205:112655. doi: 10.1016/j.ejmech.2020.112655. Epub 2020 Jul 25.

Abstract

Eukaryotic translation initiation factor 4E (eIF4E) has emerged as a promising cancer therapeutic target due to its role in the initiation of cap-dependent translation, a process that is accelerated during tumorigenesis. To regulate the initiation of cap-dependent translation, eIF4E participates in protein-protein interactions (PPI) with binding partners, 4E-BP1 and eIF4G, which act as an inhibitor and stimulator of translation, respectively. As both of these proteins interact with eIF4E by utilizing a short, α-helical stretch of amino acids, our laboratory has been working to develop helical mimetics of these proteins, in particular 4E-BP1, to inhibit eIF4E PPIs. Herein, we describe our continued efforts in this area and report the development and characterization of a cell-penetrant lactam stapled peptide for targeting cellular eIF4E.

Keywords: 4E-BP1; Protein-protein interactions; Stapled peptides; eIF4E.

MeSH terms

  • Cell Line, Tumor
  • Cell-Penetrating Peptides / chemistry*
  • Cell-Penetrating Peptides / pharmacology*
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Humans
  • Lactams / chemistry*
  • Molecular Targeted Therapy
  • Protein Binding / drug effects
  • Protein Biosynthesis

Substances

  • Cell-Penetrating Peptides
  • Eukaryotic Initiation Factor-4E
  • Lactams