1 research outputs found
Structural Optimization of Decoy Oligonucleotide-Based PROTAC That Degrades the Estrogen Receptor
Proteolysis-targeting
chimeras (PROTACs) have attracted attention
as a chemical method of protein knockdown via the ubiquitināproteasome
system. Some oligonucleotide-based PROTACs have recently been developed
for disease-related proteins that do not have optimal small-molecule
ligands such as transcription factors. We have previously developed
the PROTAC LCL-ERĀ(dec), which uses a decoy oligonucleotide
as a target ligand for estrogen receptor Ī± (ERĪ±) as a
model transcription factor. However, LCL-ERĀ(dec) has
a low intracellular stability because it comprises natural double-stranded
DNA sequences. In the present study, we developed PROTACs containing
chemically modified decoys to address this issue. Specifically, we
introduced phosphorothioate modifications and hairpin structures into LCL-ERĀ(dec). Among the newly designed PROTACs, LCL-ERĀ(dec)-H46, with a T4 loop structure at the end of the decoy, showed long-term
ERĪ± degradation activity while acquiring enzyme tolerance. These
findings suggest that the introduction of hairpin structures is a
useful modification of oligonucleotides in decoy oligonucleotide-based
PROTACs