Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins
Chenghong Zhu
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorWeishan Wang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorYan Wang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Yan Zhang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Jinbo Li
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorChenghong Zhu
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorWeishan Wang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorYan Wang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Yan Zhang
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorCorresponding Author
Prof. Jinbo Li
State 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), Nanjing University, Nanjing, 210023 China
Search for more papers by this authorAbstract
Bispecific chimeras bridging cell membrane proteins with lysosome-trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease-relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain-promoted alkyne-azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti-cancer application of NCL-targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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