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

The development of small-molecule inhibitors or stabilizers of selected protein- protein interactions (PPIs) of interest holds considerable promise for the devel-opment 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 tac-tics, with a particular focus on site-directed fragment tethering and proximity -enabled approaches.