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An ultrasonically sensitive small-molecule chimera for sono-controllable proteolysis.
Bin Zhang1, Siyi Wang1, Chen Li1
1State Key Laboratory of Analytical Chemistry for Life Sciences, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing University, Nanjing 210023, China. njuzy@nju.edu.cn.
Researchers developed an ultrasonically sensitive small-molecule chimera (USC) that conditionally degrades bromodomain-containing protein 4 (BRD4). Ultrasound triggers USC to produce singlet oxygen, enabling deep-tissue protein degradation.
Area of Science:
- Biochemistry
- Chemical Biology
- Molecular Biology
Background:
- Targeted protein degradation is a key strategy in drug discovery.
- Developing conditional and spatially controlled degradation methods is crucial for minimizing off-target effects.
- Bromodomain-containing protein 4 (BRD4) is an important epigenetic regulator implicated in various diseases.
Purpose of the Study:
- To design and synthesize an ultrasonically sensitive small-molecule chimera (USC) for targeted protein degradation.
- To demonstrate the efficacy of USC-mediated degradation of BRD4.
- To compare the deep-tissue penetration and efficacy of ultrasound-induced degradation versus light-induced degradation.
Main Methods:
- Synthesis of a small-molecule chimera (USC) linking a BRD4 ligand and a sonosensitizer.
- Ligand-guided anchoring of USC onto BRD4.
- Sonoirradiation to activate the sonosensitizer and generate singlet oxygen.
- Assessment of BRD4 degradation using biochemical and cellular assays.
- Comparison of ultrasound and near-infrared light for deep-tissue proteolysis.
Main Results:
- Successful synthesis of the USC capable of binding BRD4.
- Ultrasound irradiation of USC led to the production of singlet oxygen.
- Singlet oxygen generated by USC induced specific degradation of BRD4.
- Ultrasound demonstrated superior efficacy for deep-tissue proteolysis compared to near-infrared light.
Conclusions:
- USC represents a novel, monospecific, and conditional protein degrader activated by ultrasound.
- This technology offers a promising approach for targeted protein degradation in deep tissues.
- Ultrasound-mediated degradation provides advantages over light-based methods for in vivo applications.
