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Synthetic Condensates and Cell-Like Architectures from Amphiphilic DNA Nanostructures
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Liquid-Phase Synthesis of DNA Aptamer-Based PROTACs Using the Postsynthesis Conjugation Method.

Hitomi Terauchi1,2, Genichiro Tsuji2, Yosuke Demizu1,2,3

  • 1Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Current Protocols
|May 26, 2026
PubMed
Summary
This summary is machine-generated.

Aptamers offer a novel approach for developing Proteolysis-Targeting Chimeras (PROTACs), especially for challenging protein targets. This study details the synthesis of aptamer-PROTACs, including nuclease-resistant variants, for targeted protein degradation.

Keywords:
CuAACDNA solid‐phase synthesisPROTACnucleic acid conjugation

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteolysis-targeting chimeras (PROTACs) enable targeted protein degradation but face ligand limitations for difficult targets.
  • Aptamers, with their high affinity and specificity, present an alternative to traditional ligands in PROTAC design.

Purpose of the Study:

  • To report the synthesis of DNA aptamer-based PROTACs targeting estrogen receptor alpha (ERα).
  • To develop nuclease-resistant aptamer-PROTACs using phosphorothioate (PS) modifications.

Main Methods:

  • Solid-phase synthesis of DNA aptamers and their conjugation to E3 ligase ligands.
  • Copper-catalyzed click chemistry for assembling aptamer-PROTAC conjugates.
  • Synthesis of PS-modified aptamer-PROTAC analogues.

Main Results:

  • Successful synthesis of chimeric molecules linking ERα-binding aptamers with E3 ligase ligands.
  • Development of PS-modified aptamer-PROTACs with enhanced stability and cellular uptake.
  • Demonstration of aptamer-PROTACs as a viable strategy for targeted protein degradation.

Conclusions:

  • Aptamer-based PROTACs provide a versatile platform for targeting proteins, including transcription factors.
  • PS modifications improve the pharmacokinetic properties of aptamer-PROTACs.
  • This protocol facilitates the development of novel therapeutic strategies utilizing aptamer-PROTACs.