Programmable translational inhibition by a molecular glue-oligonucleotide conjugate

Selective inhibition of mRNA translation is a promising strategy for modulating the activity of disease-associated genes, yet achieving both high potency and specificity remains challenging. Rocaglamide A (RocA), a molecular glue, inhibits translation by clamping eIF4A onto polypurine motifs found in many transcripts, thereby limiting RocAs specificity. Here, we developed RocASO, a chemical conjugate that links RocA to an antisense oligonucleotide (ASO) capable of base-pairing with defined mRNA sequences, thus directing RocAs clamping mechanism to chosen targets and enhancing overall potency and specificity. We show that RocASOs are compatible with various types of ASO modalities, including gapmers that induce the degradation of target RNAs. RocASOs were designed to effectively knock down endogenous genes (PTGES3, HSPA1B) and SARS-CoV-2 viral RNA, the latter conferring potent antiviral activity in cells. These findings establish RocASO as a versatile platform for programmable translational inhibition with therapeutic potential.