Programmed Targeted Protein Degradation Via DNA Modularized Ligand.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis targeting chimeras (PROTACs) offer a novel therapeutic modality for targeted protein degradation.
• Current PROTAC development faces challenges in chemical synthesis and linker optimization.

Purpose of the Study:

• To present a proof-of-concept for a modular DNA-PROTAC method.
• To demonstrate a DNA-based ligand modularization strategy for PROTAC construction.
• To facilitate programmatic discovery of new PROTAC molecules.

Main Methods:

• Construction and validation of DNA-PROTACs targeting bromodomain-containing protein 4 (BRD4) and silent mating type information regulation 2 homolog-2 (Sirt2).
• Assessment of BRD4 degradation kinetics in HeLa cells using time-course experiments.
• Systematic introduction of design, synthesis, and mechanism of action for BRD4 and Sirt2 DNA-PROTACs.

Main Results:

• Successful identification and validation of functional BRD4 and Sirt2 DNA-PROTACs.
• Demonstration of DNA-PROTACs' effectiveness in targeted protein degradation.
• Establishment of a modular DNA-based platform for PROTAC development.

Conclusions:

• The DNA-PROTAC strategy offers a promising new approach for PROTAC development.
• This method may streamline linker design and ligand screening processes for PROTACs.
• The findings pave the way for accelerated discovery of novel protein degradation therapeutics.