Development of a Small Hybrid Molecule That Mediates Degradation of His-Tag Fused Proteins

In recent years, the induction of
target–protein degradation
via the ubiquitin–proteasome system (UPS) mediated by small
molecules has attracted attention, and this approach has applications
in pharmaceutical development. However, this technique requires a
ligand for the target protein that can be incorporated into tailor-made
molecules, and there are many proteins for which such ligands have
not been found. In this study, we developed a protein-knockdown method
that recognizes a His-tag fused to a protein of interest. This strategy
theoretically allows comprehensive targeting of proteins of interest
by a particular molecule recognizing the tag. As expected, our hybrid
molecule 10 [SNIPER­(CH6)] efficiently degraded His-tagged
CRABP-II and Smad2 in cells. This system provides an easy method to
determine the susceptibility of proteins of interest to UPS-mediated
degradation. Furthermore, we hope that this method will become an
efficient tool to analyze the function of the UPS.