Targeted Extracellular Protein Degradation by Dendronized DNA Chimeras

• Published in: ACS chemical biology Vol. 19; no. 3; pp. 654 - 659
• Main Authors: Zhu, Chenghong, Wang, Weishan, Wang, Yan, Zhang, Weijie, Zhang, Yan, Li, Jinbo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15.03.2024
• Subjects: Cell Proliferation; Dendrimers - pharmacology; DNA; Matrix Metalloproteinase 9; Proteolysis
• ISSN: 1554-8929; 1554-8937; 1554-8937
• DOI: 10.1021/acschembio.3c00645

Extracellular soluble proteins are key agents in the development of various diseases. However, strategies to remove therapeutically relevant extracellular targets are still scarce. Here, we establish dendronized DNA chimera (DENTAC) as an efficient approach for targeted degradation of the extracellular protein of interest (ePOI). DENTAC consists of a DNA dendron against cell-surface scavenger receptors (SRs), a protein ligand, and a connecting linker, which harnesses SRs as a lysosome-trafficking receptor to mediate the lysosomal degradation of the ePOI. We interrogate and optimize structure–activity relationships of DENTAC. Using neutravidin as a model ePOI, we show that both branch number and DNA length in the DNA dendron are important determinants for efficient lysosomal delivery and degradation of the protein. We demonstrate three branches and 10 nucleotide-length polythymidine as the optimal DNA dendron components to construct DENTAC. We further exemplify the anticancer application of DENTAC by targeting matrix metalloproteinase-9 (MMP-9), where we find linker property as another factor important for DENTAC performance. We reveal that MMP-9-targeting DENTAC effectively restrain cancer cell proliferation, migration, and invasion. This study thus provides a potent strategy to delete extracellular proteins that are commonly difficult to target.