A CYFIP1-Inspired Peptidomimetic Modulates eIF4E-Dependent Translational Control in Cancer and Neurodevelopmental Disorders

Romagnoli, A.; Alsina, O.; Raniolo, S.; Gori, A.; Foka, K.; De Luca, A.; Sgrignani, J.; Rexha, J.; Roscioni, A.; Bergamaschi, G.; Boussadia, Z.; Pepponi, R.; Venturini, G.; Cavalli, A.; Borsello, T.; Martire, A.; La Teana, A.; Bagni, C.; Di Marino, D.; Limongelli, V.

doi:10.64898/2026.05.06.722988

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bioRxiv · 10.64898/2026.05.06.722988

A CYFIP1-Inspired Peptidomimetic Modulates eIF4E-Dependent Translational Control in Cancer and Neurodevelopmental Disorders

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Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is a central regulator of cap-dependent translation and a compelling pharmacological target in disorders marked by protein synthesis dysregulation, including cancer and Fragile X Syndrome (FXS). Among endogenous eIF4E regulators, the CYFIP1-eIF4E interaction is uniquely selective, offering a framework for designing targeted translation modulators. Here, we report Cy-9B, a rationally engineered, stapled peptidomimetic derived from CYFIP1 that binds eIF4E, disrupts eIF4E-eIF4G complex, and suppresses cap-dependent translation. Enhanced-sampling free-energy simulations reveal that Cy-9B engages eIF4E through a non-canonical binding mode. Cy-9B exhibits drug-like properties, including high proteolytic stability and nanomolar affinity. Functionally, Cy-9B inhibits lung cancer cell proliferation, migration, and invasion. In neurodevelopmental disease models, Cy-9B partially normalizes excessive translation in FXS hippocampal neurons and rescues social behavior deficits in a Cyfip1 haploinsufficient Drosophila melanogaster model, restoring wild-type-like performance. Cy-9B emerges as a first-in-class therapeutic candidate for disorders sharing translational dysregulation, highlighting targeted modulation of eIF4E as a broadly applicable and physiologically compatible therapeutic strategy.

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Romagnoli, A., Alsina, O., Raniolo, S., Gori, A., Foka, K., De Luca, A., Sgrignani, J., Rexha, J., Roscioni, A., Bergamaschi, G., Boussadia, Z., Pepponi, R., Venturini, G., Cavalli, A., Borsello, T., Martire, A., La Teana, A., Bagni, C., Di Marino, D., Limongelli, V.. 2026-05-08. A CYFIP1-Inspired Peptidomimetic Modulates eIF4E-Dependent Translational Control in Cancer and Neurodevelopmental Disorders. https://doi.org/10.64898/2026.05.06.722988

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