Challenges in Therapeutically Targeting the RNA-Recognition Motif

The RNA recognition motif (RRM) is the most common RNA binding domain found in the human proteome. RRM domains provide RNA-binding proteins with sequence specific RNA recognition allowing them to participate in RNA-centric processes such as mRNA maturation, translation initiation, splicing, and RNA degradation. They are drivers of various diseases through overexpression or mutation, making them attractive therapeutic targets and addressing these proteins through their RRM domains with chemical compounds is gaining ever more attention. However, it is still very challenging to find selective and potent RNA-competitors due to the small size of the domain and high structural conservation of its RNA binding interface. Despite these challenges, a selection of compounds has been reported for several RRM containing proteins, but often with limited biophysical evidence and low selectivity. A solution to selectively targeting RRM domains might be through avoiding the RNA-binding surface altogether, but rather look for composite pockets formed with other proteins or for protein-protein interaction sites that regulate the target's activity but are less conserved. Alternative modalities, such as oligonucleotides, peptides, and molecular glues, are exciting new approaches to address these challenging targets and achieve the goal of therapeutic intervention at the RNA regulatory level.