Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Area of Science:

• Drug Discovery and Development
• Structural Biology
• Molecular Medicine

Background:

• Protein-protein interactions (PPIs) are crucial in cellular processes.
• Stabilizing specific PPIs offers therapeutic potential, exemplified by existing drugs.
• Rational design of small-molecule PPI stabilizers remains challenging.

Purpose of the Study:

• To explore a fragment-based approach for developing small-molecule stabilizers of PPIs.
• To identify starting points for molecules that can differentiate between distinct PPI interfaces.
• To target the adapter protein 14-3-3 and its interactions with p53 and TAZ.

Main Methods:

• Fragment-based drug discovery.
• X-ray crystallography to determine binding modes.
• Characterization of small molecules binding to 14-3-3 protein interfaces.

Main Results:

• Identified fragments that discriminately bind to the 14-3-3 interface.
• Demonstrated differential binding to 14-3-3 interfaces recognizing p53 versus TAZ motifs.
• X-ray crystallography confirmed fragment binding at the interface rim.

Conclusions:

• A fragment-based strategy can yield specific small-molecule stabilizers for PPIs.
• The 14-3-3 protein's interface can be targeted differentially.
• Identified fragments serve as promising starting points for developing targeted 14-3-3 PPI stabilizers.