Proteome-wide target profiling of α-helix mimetics

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial in disease but challenging drug targets due to large, featureless interfaces.
• α-helix mimetics offer a strategy to target helix-mediated PPIs by mimicking key residues.
• Existing scaffolds lack comprehensive proteome-wide selectivity data.

Purpose of the Study:

• To directly compare the proteome-wide selectivity of three distinct α-helix mimetic scaffolds.
• To evaluate the potential of small molecule scaffolds in targeting helix-mediated protein-protein interactions.
• To identify differences in target engagement across diverse chemical classes.

Main Methods:

• Affinity-based protein profiling was employed.
• Three classes of α-helix mimetics were analyzed: N-substituted oligobenzamides, pyrrolopyrimidines, and oxopiperazines.
• Proteome-wide binding was assessed for each scaffold.

Main Results:

• Significant differences in proteome-wide selectivity were observed among the three α-helix mimetic classes.
• Each scaffold exhibited a unique binding profile across the proteome.
• This cross-comparison provides novel insights into scaffold-specific targeting.

Conclusions:

• The choice of α-helix mimetic scaffold significantly impacts proteome-wide selectivity.
• Understanding these selectivity differences is crucial for rational drug design targeting PPIs.
• Further exploration of these scaffolds can lead to more selective therapeutics.