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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

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Targeted Extracellular Protein Degradation by Dendronized DNA Chimeras.

Chenghong Zhu¹, Weishan Wang¹, Yan Wang¹

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), Nanjing University, Nanjing 210023, China.

ACS Chemical Biology

|February 8, 2024

Summary

Researchers developed dendronized DNA chimeras (DENTAC) to degrade disease-causing extracellular proteins. This novel strategy effectively targets and removes proteins like matrix metalloproteinase-9, offering a new therapeutic approach.

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Area of Science:

Biotechnology
Molecular Biology
Drug Discovery

Background:

Extracellular soluble proteins play critical roles in disease pathogenesis.
Targeted removal strategies for extracellular proteins remain limited.
Scavenger receptors (SRs) are involved in cellular uptake and trafficking.

Purpose of the Study:

To establish dendronized DNA chimera (DENTAC) as an efficient method for targeted extracellular protein degradation.
To optimize DENTAC structure for enhanced lysosomal delivery and protein clearance.
To evaluate DENTAC's therapeutic potential in cancer treatment.

Main Methods:

Design and synthesis of DENTAC constructs with varying DNA dendron structures and linker properties.
Utilizing scavenger receptors (SRs) to mediate lysosomal degradation of extracellular proteins of interest (ePOI).
Employing neutravidin as a model ePOI and matrix metalloproteinase-9 (MMP-9) for anticancer application studies.

Main Results:

Optimal DENTAC design features three branches and a 10-nucleotide polythymidine DNA length for efficient lysosomal delivery.
DENTAC effectively mediates lysosomal degradation of model extracellular proteins.
MMP-9-targeting DENTAC demonstrated significant inhibition of cancer cell proliferation, migration, and invasion.

Conclusions:

Dendronized DNA chimeras (DENTAC) represent a potent strategy for targeted degradation of extracellular proteins.
DENTAC leverages scavenger receptors for lysosomal clearance, offering a novel therapeutic avenue.
This approach shows promise for targeting difficult-to-remove extracellular disease mediators, particularly in oncology.