Biology subjects

Rexha, J.

Publications and source records attributed to Rexha, J..

2 recordsLinked to original sources

bioRxiv2026

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

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.

biochemistry↗

bioRxiv2025

Ligand-Induced Structural Dynamics Drive Allosteric Regulation of Translation Initiation Factor eIF4E

The eukaryotic initiation factor 4E (eIF4E) governs cap-dependent translation, and its dysregulation contributes both to cancer and neurological disorders, making it an attractive target for therapeutic intervention. Among the few small-molecule inhibitors developed, 4EGI-1 and its analogue i4EG-BiP have shown promise in cellular and preclinical models. These compounds disrupt eIF4Es interaction with its partner eIF4G while enhancing binding to its negative regulators, the 4E-binding proteins (4E-BPs). Despite their chemical similarity and overlapping functional effects, structural data suggest the two ligands engage different regions of eIF4E, lateral for 4EGI-1 and frontal for i4EG-BiP, raising questions about the basis of their shared activity. Here, we integrate molecular simulations, site-directed mutagenesis, and fluorescence binding assays to elucidate the mechanism of action of both ligands. Funnel metadynamics free-energy calculations reveal that the frontal binding mode is thermodynamically preferred for both compounds. Furthermore, we demonstrate that the conformational rearrangement induced by frontal binding selectively promotes 4E-BP1 over eIF4G association, explaining their common allosteric regulatory effect. These findings reconcile divergent structural observations and highlight how ligand-induced dynamics can be exploited to reprogram eIF4E interactions, offering a framework for next-generation therapeutics targeting dysregulated translation.

molecular biology↗