Aptamer and N‑Degron\nEnsemble (AptaGron) as\na Target Protein Degradation Strategy

Target protein degradation (TPD) is a promising strategy\nfor catalytic\ndownregulation of target proteins through various cellular proteolytic\npathways. Despite numerous reports on novel TPD mechanisms, the discovery\nof target-specific ligands remains a major challenge. Unlike small-molecule\nligands, aptamers offer significant advantages, owing to their SELEX-based\nsystematic screening method. To fully utilize aptamers for TPD, we\ndesigned an aptamer and N-degron ensemble system (AptaGron) that circumvents\nthe need for synthetic conjugations between aptamers and proteolysis-recruiting\nunits. In our AptaGron system, a peptide nucleic acid containing an\nN-degron peptide and a sequence complementary to the aptamer was designed.\nUsing this system, we successfully degraded three target proteins,\ntau, nucleolin, and eukaryotic initiation factor 4E (eIF4E), which\nlack specific small-molecule ligands. Our results highlight the potential\nof the AptaGron approach as a robust platform for targeted protein\ndegradation.