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

Whereas, historically, the majority of efforts toward small-molecule modulators of PPIs have largely focused on PPI inhibitors, there is growing evidence that stabilization of selected PPIs with small molecules is an achievable goal.Targeted covalent modification of amino acid residues within proteins of interest is a validated strategy that has the potential of providing both selectivity and duration of action.Different covalent labeling strategies have been developed that can facilitate the identification of small-molecule modulators of PPIs. The development of small-molecule inhibitors or stabilizers of selected protein–protein interactions (PPIs) of interest holds considerable promise for the development of research tools as well as candidate therapeutics. In this context, the covalent modification of selected residues within the target protein has emerged as a promising mechanism of action to obtain small-molecule modulators of PPIs with appropriate selectivity and duration of action. Different covalent labeling strategies are now available that can potentially allow for a rational, ground-up discovery and optimization of ligands as PPI inhibitors or stabilizers. This review article provides a synopsis of recent developments and applications of such tactics, with a particular focus on site-directed fragment tethering and proximity-enabled approaches.