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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
Summary
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.
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.
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