Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins. Issue 13 (15th February 2023)

• Record Type: Journal Article
• Authors: Zhu, Chenghong; Wang, Weishan; Wang, Yan; Zhang, Yan; Li, Jinbo
• Is Part Of: Angewandte Chemie international edition. Volume 62:Issue 13(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-15
• Subjects: Cancer Therapy -- DNA -- Membrane Proteins -- Targeted Degradation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202300694
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : A general and efficient dendronized DNA chimera (DENTAC) strategy for targeted membrane protein degradation is reported. DENTAC comprises a protein‐of‐interest (POI) binder linked with a dendritic DNA, which engages cell surface scavenger receptors (SRs) to transport the POI into the lysosome for degradation.