Targeted protein degradation using
chimeric small molecules, such
as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic
inhibitors of apoptosis protein (IAP)-dependent protein erasers (SNIPERs),
has attracted attention as a method for degrading intracellular target
proteins via the ubiquitin-proteasome system (UPS). These chimeric
molecules target a variety of proteins using small molecules that
can bind to the proteins. However, it is difficult to develop such
degraders in the absence of suitable small-molecule ligands for the
target proteins, such as for transcription factors (TFs). Therefore,
we constructed the chimeric molecule LCL-ER(dec), which
consists of a decoy oligonucleotide that can bind to estrogen receptor
α (ERα) and an IAP ligand, LCL161 (LCL), in a click reaction. LCL-ER(dec) was found to selectively degrade ERα via
the UPS. These findings will be applicable to the development of other
oligonucleotide-type degraders that target different TFs.
Targeted protein degradation (TPD), using chimeric molecules such as proteolysis-targeting chimeras (PROTACs), has attracted attention as a strategy for selective degradation of intracellular proteins by hijacking the ubiquitin-proteasome system (UPS). However, it is often difficult to develop such degraders due to the absence of appropriate ligands for target proteins. In targeting proteins for degradation, the application of nucleic acid aptamers is considered to be effective because these can be explored using systematic evolution of ligand by exponential enrichment (SELEX) methods. In this study, we constructed chimeric molecules in which nucleic acid aptamers capable of binding to the estrogen receptor α (ERα) and E3 ubiquitin ligase ligands were linked via a linker. ERα aptamer-based PROTACs were found to degrade ERα via the UPS. These findings represent the development of novel aptamer-based PROTACs that target intracellular proteins and are potentially applicable to other proteins.
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