Compact Sulfonyl-γ-AApeptide Foldamers for Targeting Translation Initiation Machinery Assembly

Abstract Dysregulated cap-dependent translation is a hallmark of malignant transformation and progression, yet direct inhibition of the dynamic eIF4E−eIF4G protein−protein interaction remains challenging. Herein, we report the rational design of short helical sulfonyl-γ-AApeptide foldamers mimicking the eIF4G1 α-helical binding motif and directly engaging eIF4E. Structure-guided optimization, including stereochemical remodeling, afforded a compact, right-handed foldamer with remarkable proteolytic stability, submicromolar affinity for eIF4E, and potent inhibition of cap-dependent translation. Recognizing that cancer cells exploit enhanced lysosome-centered signaling and trafficking programs to sustain cap-dependent translation, we repurposed this oncogenic dependency as an intracellular delivery route to release the translation inhibitor. The optimized conjugate suppresses ferritin translation, triggers lipid peroxidation and ferroptosis, and exhibits antitumor activity in vivo. Together, these findings establish short sulfonyl-γ-AApeptides as an effective chemical modality for targeting eIF4E−eIF4G interface and demonstrate that dynamic assembly events within the translation initiation machinery can be manipulated through rational foldamer design.