Harnessing BET-Bromodomain Assisted Nuclear Import for Targeted Subcellular Localization and Enhanced Efficacy of Antisense Oligonucleotides.

ABSTRACT: Antisense oligonucleotides (ASOs) are a promising class of therapeutics designed to modulate gene expression. Both key mechanisms of action for ASOs operate in the nucleus: splice-switching ASOs modify pre-mRNA, processed in the nucleus, and mRNA-degrading ASOs require RNase H, an enzyme predominantly active in the nucleus. Therefore, to achieve maximal therapeutic efficacy, ASOs require efficient nuclear delivery. In this work, we have synthesized ASO conjugates for active nuclear import, by covalent conjugation with a potent and proven small-molecule nuclear importer, (+)-JQ1. (+)-JQ1 is a well-characterized high-affinity binder for members of the BET bromodomain family of proteins and was recently shown to transport cytoplasmic proteins into the nucleus. Our (+)-JQ1-ASO conjugates outpe

SUBMITTER: Kashyap D 

PROVIDER: S-EPMC12356583 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature