Development of DNA Aptamer-Based PROTACs That Degrade the Estrogen Receptor

Targetedprotein degradation (TPD), using chimeric molecules suchas proteolysis-targeting chimeras (PROTACs), has attracted attentionas a strategy for selective degradation of intracellular proteinsby hijacking the ubiquitin-proteasome system (UPS). However, it isoften difficult to develop such degraders due to the absence of appropriateligands for target proteins. In targeting proteins for degradation,the application of nucleic acid aptamers is considered to be effectivebecause these can be explored using systematic evolution of ligandby exponential enrichment (SELEX) methods. In this study, we constructedchimeric molecules in which nucleic acid aptamers capable of bindingto the estrogen receptor alpha (ER alpha) and E3 ubiquitin ligaseligands were linked via a linker. ER alpha aptamer-based PROTACswere found to degrade ER alpha via the UPS. These findings representthe development of novel aptamer-based PROTACs that target intracellularproteins and are potentially applicable to other proteins.

Automated summary

Targeted protein degradation (TPD) using chimeric molecules like proteolysis-targeting chimeras (PROTACs) has been studied as a strategy to selectively degrade intracellular proteins by utilizing the ubiquitin-proteasome system (UPS). Nucleic acid aptamers have shown potential as ligands for targeting proteins for degradation. In this study, nucleic acid aptamers were linked to estrogen receptor alpha (ER alpha) and E3 ubiquitin ligase ligands to construct chimeric molecules that could degrade ER alpha via UPS. These findings demonstrate the development of novel aptamer-based PROTACs for targeting intracellular proteins.