Cyclic γ-AApeptide-Based Molecular Glues for RNA m⁶A Editing

The m⁶A modification plays key roles in RNA metabolism and function and is implicated in various human diseases. In this study, we reported a novel molecular glue strategy for transcript-specific m⁶A editing using synthetic bifunctional molecules containing an RNA-targeting moiety and a ligand that recruit an endogenous m⁶A erasing enzyme. Through cyclic γ-AApeptide library screening, we identified a novel peptidomimetic binder to the long noncoding RNA MALAT1 A2577 region, which has a high m⁶A level. We developed a bifunctional molecular glue by coupling the identified MALAT1-binding cyclic γ-AApeptide to fluorescein, a reported binder to the m⁶A eraser FTO. We demonstrated that this bifunctional molecular glue successfully recruited FTO to the target RNA site, achieved the m⁶A erasing, disrupted HNRNPC-MALAT1 binding, and destabilized MALAT1. We anticipate that this novel molecular glue strategy will offer a new direction in developing molecules to regulate RNA modifications.