Oligonucleotide-based PROTACs to Degrade RNA- and DNA-Binding Proteins

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce targeted protein degradation by engaging the cell's ubiquitin-proteasome system.
• PROTACs function by bringing a target protein and a ubiquitin E3 ligase into close proximity, facilitating ubiquitination and subsequent proteasomal degradation.
• Modulating the function of RNA- and DNA-binding proteins with conventional small molecules presents significant challenges.

Purpose of the Study:

• To review the current advancements and applications of oligonucleotide-based PROTACs.
• To highlight the potential of using oligonucleotides to target RNA- and DNA-binding proteins for degradation.
• To summarize the strategies for developing oligonucleotide-based PROTACs.

Main Methods:

• Utilizing oligonucleotides as ligands to bind specific RNA- or DNA-binding proteins.
• Conjugating these oligonucleotides to E3 ligase recruiters to form heterobifunctional molecules.
• Leveraging the PROTAC mechanism to induce ubiquitination and proteasomal degradation of target proteins.

Main Results:

• Oligonucleotide-based PROTACs offer a novel strategy for degrading RNA- and DNA-binding proteins.
• This approach overcomes limitations associated with small molecule inhibitors for these protein classes.
• Demonstrated efficacy in directing targeted protein degradation via the ubiquitin-proteasome pathway.

Conclusions:

• Oligonucleotide-based PROTACs represent a promising therapeutic modality for targeting previously intractable proteins.
• This technology expands the scope of targeted protein degradation beyond targets amenable to small molecule modulation.
• Further research in this area holds potential for developing new treatments for various diseases.