De Novo Designed Bifunctional Proteins for Targeted Protein Degradation

The study presents a novel approach to targeted protein degradation (TPD) by designing hetero-bifunctional de novo proteins, which can potentially overcome the limitations of current proteolysis-targeting chimeras (PROTACs). The researchers developed a stable helix-turn-helix scaffold capable of presenting various binding sites and used computational protein design to target the BCL-xL protein and recruit the KLHL20 ligase. These designed proteins successfully bind to targets in vitro and degrade BCL-xL in cells, inducing apoptosis, thus offering a promising alternative for expanding the range of targets and ligases in TPD strategies.