Short helical sulfonyl-γ-AApeptide foldamers disrupt eIF4E-eIF4G and, as a lysosome-directed conjugate, induce ferroptosis and antitumor effects
- Short helical sulfonyl-γ-AApeptides were designed to mimic the eIF4G1 alpha-helical motif and bind eIF4E directly.
- Structure-guided stereochemical remodeling gave a compact right-handed foldamer with strong proteolytic stability, submicromolar affinity and potent inhibition of cap-dependent translation.
- Exploiting lysosome-centered signaling in cancer cells, a conjugate delivered the inhibitor intracellularly.
- The conjugate suppressed ferritin translation, causing lipid peroxidation, ferroptosis and in vivo antitumor activity.
💡 Points Based on the abstract
Helical foldamers beat stapled peptides on protease stability, but submicromolar affinity is modest next to eIF4E's cap-site binders, and the cell story rests on a lysosome-directed conjugate. Where is the control? I'd want an inactive stereoisomer conjugate and a ferroptosis rescue with iron chelation or ferrostatin, to show effects come from eIF4E blockade rather than the carrier.
Compact Sulfonyl-γ-AApeptide Foldamers for Targeting Translation Initiation Machinery Assembly ↗