Localized 2′-OH Acylation at Poly(A) Extends RNA Translation

The potential of coding RNAs as a general therapeutic modality is limited by their short intracellular lifetime. Here, we investigate the effects of localized post-transcriptional RNA modification on protein expression over time. While 2′-OH acylation of GFP RNA with stable adducts in the protein-coding region strongly suppressed protein expression, acylation at the poly(A) tail extended translation duration, with protein output increased by up to 8-fold at 36 h. Aryl amino acid derivatives proved to be most effective, while alkyl variants showed little effect. Preliminary mechanistic experiments point to disruption of the poly(A) helical structure as a contributing factor. Our study demonstrates the potential of post-transcriptional localized 2′-acylation as a simple molecular solution to enhance protein-expression capabilities of RNAs.