Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial in cellular processes and are key targets for therapeutic intervention.
• Developing small molecules to modulate PPIs offers significant potential for novel research tools and drug candidates.
• Achieving selectivity and appropriate duration of action for PPI modulators remains a challenge.

Purpose of the Study:

• To review recent advancements in covalent labeling strategies for modulating protein-protein interactions (PPIs).
• To highlight the application of these tactics in discovering and optimizing small-molecule PPI inhibitors and stabilizers.
• To focus on site-directed fragment tethering and proximity-enabled approaches.

Main Methods:

• Review of literature on covalent modification strategies for PPI modulation.
• Synopsis of recent developments in site-directed fragment tethering.
• Analysis of proximity-enabled approaches for ligand discovery.

Main Results:

• Covalent modification of proteins provides a robust mechanism for creating selective and durable small-molecule PPI modulators.
• Various covalent labeling strategies enable rational design and optimization of ligands.
• Site-directed fragment tethering and proximity-enabled methods show significant promise.

Conclusions:

• Covalent strategies represent a powerful approach for developing small-molecule modulators of PPIs.
• These methods facilitate the discovery of targeted research tools and potential therapeutics.
• Further exploration of covalent tactics will advance the field of PPI modulation.