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bioRxiv · 10.64898/2026.03.09.710667

A Dimeric Rocaglate Promotes Multivalent eIF4A-RNA Assembly

Shokat, K.·Liu, J.·Moore, M. K.·Lou, K.·Wassarman, D. R.·Arab, A.·Ojeda, S.·Karakyriakou, B.·Koglin, A.-S.·Ott, C. J.·Gilbert, L.
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Abstract

Ligand dimerization represents a powerful strategy to enhance avidity, potency, and selectivity. Leveraging the natural-product molecular glue Rocaglamide (RocA), we identified BisRoc, a dimeric rocaglate ligand that potently and durably suppresses translation and exhibits greater specificity across a cancer cell line panel than the monomeric RocA. CRISPRi screening revealed that BisRoc activity is influenced by cellular context, including IFITM-mediated uptake, ABC-type efflux transporters, and the translation initiation factor eIF4A2. Mechanistic studies showed that the paralogs eIF4A1 and eIF4A2 are differentially sensitive to BisRoc-induced dimerization. Owing to the presence of multiple binding sites on RNAs, BisRoc-bridged eIF4A-RNA motifs assemble into higher-order complexes that promote stress-granule formation more efficiently than monomeric RocA. Given the widespread multivalency of RNA-RBP interactions, this ligand dimerization strategy may be extended to modulate the higher-order assembly of other RNA-binding proteins. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/710667v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1f0ce69org.highwire.dtl.DTLVardef@7f7fadorg.highwire.dtl.DTLVardef@976e81org.highwire.dtl.DTLVardef@1d7eaf2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Shokat, K., Liu, J., Moore, M. K., Lou, K., Wassarman, D. R., Arab, A., Ojeda, S., Karakyriakou, B., Koglin, A.-S., Ott, C. J., Gilbert, L.. 2026-03-10. A Dimeric Rocaglate Promotes Multivalent eIF4A-RNA Assembly. https://doi.org/10.64898/2026.03.09.710667

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