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Protease-Responsive Toolkit for Conditional Targeted Protein Degradation.

Hopen Yang1, Wilfred Chen1

  • 1Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware 19716, United States.

ACS Synthetic Biology
|June 18, 2024
PubMed
Summary
This summary is machine-generated.

Researchers developed dynamic bioPROTACs for controlled protein degradation. This new system uses protease control switches to fine-tune target protein levels, offering a versatile therapeutic approach.

Keywords:
E3 ligasemodularsynthetic biologytargeted protein degradation

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Area of Science:

  • Biotechnology
  • Molecular Biology
  • Proteomics

Background:

  • BioPROTACs (heterobifunctional proteins) enable targeted protein degradation for therapeutic applications.
  • Current bioPROTAC strategies are static, lacking dynamic control over protein degradation.
  • Dynamic modulation of disease-related proteins is crucial for advanced therapeutic interventions.

Purpose of the Study:

  • To introduce a synthetic framework for dynamic fine-tuning of target protein levels using protease control switches.
  • To develop conditional targeted protein degradation systems by interfacing exogenous inputs with protease-mediated recruitment.
  • To demonstrate the adaptability of this novel bioPROTAC framework.

Main Methods:

  • Designed bioPROTACs with separated binding domains, utilizing proteases as an interfacing layer.
  • Employed TEV protease as a transducer to link small-molecule and optogenetic inputs to protein degradation.
  • Adapted two efficient bioPROTAC systems, AdPROM and IpaH9.8-based Ubiquibodies, for protease-responsive control.

Main Results:

  • Demonstrated successful dynamic fine-tuning of target protein levels via protease control.
  • Showcased conditional targeted protein degradation by interfacing external inputs (small molecules, light) with bioPROTACs.
  • Validated the adaptability and modularity of the protease-responsive bioPROTAC design.

Conclusions:

  • BioPROTACs with protease-responsive linkers offer a versatile platform for conditional targeted protein degradation.
  • This framework enables dynamic control over protein levels, expanding therapeutic possibilities.
  • The decoupled design allows for easy adaptation of new conditional degradation phenotypes.