Aptamer and N-Degron Ensemble (AptaGron) as a Target Protein Degradation Strategy

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Target protein degradation (TPD) offers a novel therapeutic strategy by catalytically downregulating proteins.
• Identifying specific ligands for TPD remains a significant hurdle, limiting its broader application.
• Aptamers, selected via SELEX, present advantages over small molecules for TPD due to their systematic screening.

Purpose of the Study:

• To develop a novel aptamer-based system for targeted protein degradation (TPD).
• To overcome the limitations of synthetic conjugation in existing TPD strategies.
• To demonstrate the efficacy of the new system against challenging target proteins lacking small-molecule ligands.

Main Methods:

• Design of an aptamer and N-degron ensemble system (AptaGron).
• Utilized a peptide nucleic acid incorporating an N-degron peptide and an aptamer-complementary sequence.
• Applied the AptaGron system to induce degradation of specific target proteins in cellular models.

Main Results:

• Successfully demonstrated targeted degradation of three proteins: tau, nucleolin, and eukaryotic initiation factor 4E (eIF4E).
• The AptaGron system effectively bypassed the need for direct synthetic conjugation between aptamers and proteolysis-recruiting units.
• Validated the system's capability to degrade proteins that lack established small-molecule ligands.

Conclusions:

• The AptaGron system represents a robust and versatile platform for aptamer-mediated targeted protein degradation.
• This approach expands the potential of aptamers in TPD, particularly for targets previously inaccessible to small-molecule ligands.
• Highlights a promising new strategy for developing therapeutics based on catalytic protein downregulation.