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DNA-Programmable Protein Degradation: Dynamic Control of Proteolysis-Targeting Chimera Activity via DNA Hybridization
Disha Kashyap1,2, Shozeb Haider3,4,5, Thomas A Milne2
1Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
JACS Au
|August 29, 2025
Summary
DNA nanotechnology enables precise control over proteolysis-targeting chimeras (PROTACs). Oligonucleotide-linked PROTACs (OligoPROTACs) offer distance-dependent degradation and a dynamic off-switch, enhancing therapeutic safety and function.
Area of Science:
- Biotechnology
- Molecular Biology
- Drug Discovery
Background:
- Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers therapeutic advantages but faces challenges in controlling off-target effects.
- Traditional PROTAC chemistries limit precise activity control, necessitating novel approaches for enhanced safety and selectivity.
Purpose of the Study:
- To design and characterize oligonucleotide-linked PROTACs (OligoPROTACs) for precise, controllable protein degradation.
- To demonstrate a dynamic off-switch mechanism for PROTAC activity using DNA nanotechnology.
Main Methods:
- Covalent linkage of PROTAC warheads to complementary DNA strands to form OligoPROTACs.
- Utilizing DNA hybridization to bring PROTAC components into proximity.
- Employing toehold-mediated strand displacement for dynamic control of PROTAC activity.
Main Results:
- OligoPROTACs demonstrate distance-dependent degradation of the target protein of interest (POI).
- A novel, dynamic off-switch mechanism for PROTAC activity was successfully implemented using DNA strand displacement.
- The study showcases the potential of DNA nanotechnology for refining PROTAC functionality.
Conclusions:
- DNA nanotechnology provides unprecedented programmability for controlling PROTAC activity.
- OligoPROTACs represent a significant advancement in developing safer and more effective targeted protein degradation therapeutics.
- This approach merges DNA nanotechnology with nucleic acid therapeutics for improved clinical translation.
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