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DNA framework-engineered chimeras platform enables selectively targeted protein degradation.

Li Zhou1, Bin Yu2, Mengqiu Gao1

  • 1Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, China.

Nature Communications
|July 26, 2023
PubMed
Summary

Researchers developed DNA framework-based PROTACs (DbTACs) for precise protein degradation. This universal platform enables high-throughput synthesis and tunable ligand spacing for efficient and selective target depletion.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Developing proteolysis targeting chimeras (PROTACs) requires a universal platform for precise protein of interest (POI) degradation.
  • Existing PROTAC development faces challenges in broad applicability and efficient synthesis.

Purpose of the Study:

  • To engineer a universal platform for PROTAC development using DNA frameworks.
  • To demonstrate the efficacy of DNA framework-based PROTACs (DbTACs) in targeted protein degradation.

Main Methods:

  • Utilized DNA tetrahedra as rigid templates for precise spatial arrangement of POI and E3 ligase ligands.
  • Employed facile bioorthogonal chemistry and self-assembly for high-throughput synthesis of DbTACs.
  • Manipulated ligand spacing from 8 Å to 57 Å and tested various warheads (small molecules, antibodies, DNA motifs).

Main Results:

  • DbTACs with optimized linker lengths showed increased degradation rates and binding affinity.
  • Bispecific DbTACs enabled multi-target depletion and selective degradation of protein subtypes.
  • DbTACs demonstrated robust efficacy in degrading diverse targets like kinases and transcription factors in various cellular compartments.

Conclusions:

  • Modular DNA frameworks offer a universal platform for conjugating substrates in PROTAC development.
  • DbTACs provide insights into general degrader design principles and present a promising strategy for drug discovery.