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Updated: Dec 27, 2025
Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
Light-induced control of protein destruction by opto-PROTAC
Jing Liu1, He Chen2, Leina Ma1
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light-inducible switch on PROTACs, thereafter termed as opto-PROTAC, to enable the degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light-inducible protein degradation. These opto-PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light-controlled PROTACs and enables PROTAC to be a precision medicine.
Insights
Researchers developed opto-PROTACs, light-inducible Proteolysis Targeting Chimeras, for controlled protein degradation. This innovation allows spatiotemporal targeting, overcoming toxicity issues and advancing PROTACs for precision medicine.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Proteolysis Targeting Chimeras (PROTACs) offer a novel therapeutic strategy by hijacking the ubiquitin-proteasome system for targeted protein degradation.
- The catalytic activity of PROTACs can lead to uncontrolled degradation and systemic toxicity, limiting their clinical application.
Purpose of the Study:
- To develop a light-inducible PROTAC system (opto-PROTAC) for spatiotemporal control over protein degradation.
- To demonstrate the efficacy and safety of opto-PROTACs in a controlled manner.
Main Methods:
- Incorporation of a photolabile caging group onto the ligand of existing PROTAC molecules (pomalidomide, dBET1, dALK).
- Assessment of opto-PROTAC activity under dark conditions versus ultraviolet A (UVA) irradiation.
- Evaluation of spatiotemporal control over protein degradation induction.
Main Results:
- Opto-PROTACs exhibited no degradation activity in the dark, ensuring target specificity.
- Light-induced, controlled protein degradation was achieved with specific timing and rate via UVA irradiation.
- Demonstrated successful application with modified pomalidomide, dBET1, and dALK PROTACs.
Conclusions:
- The developed opto-PROTAC platform enables precise, light-controlled protein degradation.
- This approach offers a generalizable strategy to mitigate PROTAC-associated toxicities.
- Opto-PROTACs represent a significant advancement towards the clinical application of PROTACs in precision medicine.
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