Consideration of Binding Kinetics in the Design of Stapled Peptide Mimics of the Disordered Proteins Eukaryotic Translation Initiation Factor 4E-Binding Protein 1 and Eukaryotic Translation Initiation Factor 4G

Protein disorder plays a crucial
role in signal transduction and
is key for many cellular processes including transcription, translation,
and cell cycle. Within the intrinsically disordered protein interactome,
the α-helix is commonly used for binding, which is induced via
a disorder-to-order transition. Because the targeting of protein–protein
interactions (PPIs) remains an important challenge in medicinal chemistry,
efforts have been made to mimic this secondary structure for rational
inhibitor design through the use of stapled peptides. Cap-dependent
mRNA translation is regulated by two disordered proteins, 4E-BP1 and
eIF4G, that inhibit or stimulate the activity of the m7G cap-binding translation initiation factor, eIF4E, respectively.
Both use an α-helical motif for eIF4E binding, warranting the
investigation of stapled peptide mimics for manipulating eIF4E PPIs.
Herein, we describe our efforts toward this goal, resulting in the
synthesis of a cell-active stapled peptide for further development
in manipulating aberrant cap-dependent translation in human diseases.