Nucleic-Acid-Based Targeted Degradation in Drug Discovery

Targeted protein degradation (TPD), represented by proteolysis-targeting chimera (PROTAC), has emerged as a novel therapeutic modality in drug discovery. However, the application of conventional PROTACs is limited to protein targets containing cytosolic domains with ligandable sites. Recently, nucleic-acid-based modalities, such as modified oligonucleotide mimics and aptamers, opened new avenues to degrade protein targets and greatly expanded the scope of TPD. Beyond constructing protein-degrading chimeras, nucleic acid motifs can also serve as substrates for targeted degradation. Particularly, the new type of chimeric RNA degrader termed ribonuclease-targeting chimera (RIBOTAC) has shown promising features in drug discovery. Here, we provide an overview of the newly emerging TPD strategies based on nucleic acids as well as new strategies for targeted degradation of nucleic acid (RNA) targets. The design strategies, case studies, potential applications, and challenges are focused on.