Coiled-coil scaffolds for Targeted Protein Degradation

In targeted protein degradation (TPD) the cells quality control machinery is co-opted to degrade proteins of interest. Currently TPD is limited by the availability of small-molecule binders for targets and the many potential human E3 ubiquitin ligases. Consequently, other approaches are needed to tackle new targets and to exploit degradation pathways fully. The natural binding epitopes for E3s and other degradation machineries are often short linear peptide motifs, which offer routes to new biologics-based degraders. Here, targeting the anti-apoptotic BCL-xL and initiation of apoptosis, we show that several protein-degradation pathways--ubiquitination, direct proteasome, autophagy-lysosome recruitment--can be leveraged by integrating target-binding and degradation motifs into single-polypeptide constructs. This exploits versatile and varied de novo coiled-coil scaffolds as adaptable molecular glues by presenting motifs multivalently and in diverse arrangements. The constructs are small ({approx}80 residues) and provide a plug-and-play platform to map and optimise target-degradation space using rational design. We call this Coiled Coils for induced Proximity (CoCoProx) and propose its use for targeted degradation and other induced-proximity reactions.