Design of bifunctional molecules to accelerate post-translational modifications: achievements and challenges

Post-translational modifications (PTMs) of proteins are crucial for regulating biological processes and their dysregulation is linked to various diseases, highlighting PTM regulation as a significant target for drug development. Traditional drug targets often interact with multiple proteins, resulting in lower selectivity and inevitable adverse effects, which limits their clinical applicability. Recent advancements in bifunctional molecules, such as proteolysis-targeting chimeras (PROTACs), have shown promise in targeting PTMs precisely. However, regulatory mechanisms for many of the >600 known PTMs remain underexplored. This review examines current progress and challenges in designing bifunctional molecules for PTM regulation, focusing on effector selection and ligand design strategies, aiming to propel the utilization and advancement of bifunctional molecules to the forefront of PTM research.