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 to target due to large, featureless interfaces.
• α-helix mimetics offer a strategy to target helix-mediated PPIs by mimicking key residues.
• Existing helix mimetics 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 challenging protein-protein interactions.
• To provide insights into scaffold selection for drug discovery targeting PPIs.

Main Methods:

• Affinity-based protein profiling was employed.
• Three structurally distinct α-helix mimetic classes were profiled: N-substituted oligobenzamides, pyrrolopyrimidines, and oxopiperazines.
• Proteome-wide binding selectivity was assessed for each scaffold class.

Main Results:

• Significant differences in proteome-wide selectivity were observed across the three α-helix mimetic scaffolds.
• N-substituted oligobenzamides, pyrrolopyrimidines, and oxopiperazines exhibit unique binding profiles.
• This study provides the first direct cross-comparison of these helix mimetic scaffolds.

Conclusions:

• The choice of α-helix mimetic scaffold significantly impacts target selectivity across the proteome.
• Understanding scaffold-specific selectivity is crucial for the rational design of PPI-targeting therapeutics.
• These findings advance the development of small molecules for targeting dysregulated protein-protein interactions in disease.