Molecularly Imprinted Polymers for Highly Specific Bioorthogonal Catalysis Inside Cells
Zhiguo Gao1,2, Quanlin Shao2, Jiaqi Xing2
1School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 210089, China.
We developed copper-containing molecularly imprinted enzyme mimics (Cu-MIEs) for precise bioorthogonal catalysis within cells. These Cu-MIEs effectively cleave specific substrates, enabling applications like drug activation and gene expression control.
Area of Science:
- Biochemistry
- Chemical Biology
- Synthetic Chemistry
Background:
- Transition metal catalysts (TMCs) are crucial for bioorthogonal catalysis, enabling new chemical reactions within living systems.
- Developing synthetic catalysts that mimic the efficiency and specificity of natural metalloenzymes remains a significant challenge.
Purpose of the Study:
- To explore the potential of molecularly imprinted enzyme mimics (MIEs) with a copper (Cu) center for specific substrate cleavage within cells.
- To engineer Cu-MIEs for enhanced activity and broader substrate scope in cellular environments.
- To demonstrate the application of Cu-MIEs in a biologically relevant system, such as a drug-activated gene switch.
Main Methods:
- Design and synthesis of Cu-containing MIEs with substrate-specific binding domains.
- In vitro and in cellulo evaluation of Cu-MIEs' catalytic activity and specificity, particularly in glutathione (GSH)-rich environments.
- Adaptation of MIE templates to optimize catalytic efficiency and expand substrate recognition.
- Application of the Cu-MIE system to a thyroid hormone (T3)-responsive gene expression model.
Main Results:
- Cu-MIEs demonstrated high specificity in catalyzing dimethylpropargyloxycarbonyl (DmProc) cleavage, even in the presence of high GSH concentrations.
- Tailoring MIE templates led to significantly enhanced catalytic activity and enabled the targeting of diverse substrates.
- The Cu-MIE system successfully activated T3 prodrugs in a cellular context, leading to T3-mediated firefly luciferase expression.
- This demonstrates the seamless integration of engineered MIEs into cellular biocatalytic networks.
Conclusions:
- Cu-MIEs represent a promising class of synthetic catalysts for precise bioorthogonal reactions in cellular environments.
- The templating strategy offers a versatile approach to engineer MIEs for specific biocatalytic tasks.
- This work validates the potential of MIEs for applications in chemical biology, including prodrug activation and controlled gene regulation.
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