Targeted degradation via direct 26S proteasome recruitment

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Targeted protein degradation is a promising therapeutic strategy.
• Current methods rely on ubiquitin ligases, limiting their application.
• The 26S proteasome is a universal cellular degradation machine with few known ligands.

Purpose of the Study:

• To develop a new targeted protein degradation strategy.
• To identify ligands that directly recruit substrates to the 26S proteasome.
• To demonstrate the efficacy of direct proteasomal recruitment for protein degradation.

Main Methods:

• Identification of peptidic macrocycles binding to the 26S proteasome subunit PSMD2.
• Cryo-electron microscopy for structural analysis of the proteasome-ligand complex.
• Conjugation of proteasome-binding macrocycles to a BRD4 ligand.

Main Results:

• Discovery of potent peptidic macrocycles that bind directly to PSMD2.
• 2.5-Å-resolution cryo-electron microscopy structure revealed the binding site near the 26S proteasome pore.
• Chimeric molecules effectively degraded BRD4 in cells via direct proteasomal recruitment.

Conclusions:

• Direct substrate recruitment to the 26S proteasome is a viable strategy for targeted protein degradation.
• This approach overcomes limitations of ubiquitin ligase-dependent methods.
• The identified macrocycles provide a foundation for developing new therapeutics.