Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Eukaryotic initiation factor 4E (eIF4E) is a therapeutic target overexpressed in cancers.
• eIF4E binds the 5' cap of mRNA, initiating cancer-specific protein synthesis.
• Disulphide constrained peptides targeting eIF4E face challenges with cell permeability and stability.

Purpose of the Study:

• To develop a cell-permeable molecule targeting the eIF4E cap-binding site.
• To overcome limitations of peptide-based inhibitors for intracellular targets.
• To identify novel therapeutic strategies for cancer by modulating eIF4E function.

Main Methods:

• Peptide epitope linker evolution (PELE) was employed to engineer a VH domain.
• The cap-binding motif was incorporated into a VH domain's hypervariable loop.
• Selections were performed to identify molecules with high affinity for eIF4E.

Main Results:

• A novel VH domain was identified with nanomolar affinity for the eIF4E cap-binding site.
• The VH domain demonstrated intracellular expression in mammalian cells.
• The molecule effectively decreased cap-dependent translation and cyclin D1 expression, modulating eIF4E function.

Conclusions:

• A novel, intracellularly expressed VH domain effectively targets eIF4E.
• This engineered molecule represents a promising therapeutic candidate for cancers overexpressing eIF4E.
• Modulating eIF4E function via this approach offers a new avenue for cancer treatment.