1 research outputs found
Boc<sub>3</sub>Arg-Linked Ligands Induce Degradation by Localizing Target Proteins to the 20S Proteasome
Targeted protein degradation is a
promising strategy for drug design
and functional assessment. Several small molecule approaches have
been developed that localize target proteins to ubiquitin ligases,
inducing ubiquitination and subsequent degradation by the 26S proteasome.
We discovered that the degradation of a target protein can also be
induced by a recognition ligand linked to <i>tert</i>-butyl
carbamate (Boc<sub>3</sub>)-protected arginine (B<sub>3</sub>A). Here,
we show that this process requires the proteasome but does not involve
ubiquitination of the target protein. B<sub>3</sub>A does not perturb
the structure of the target protein; instead, a B<sub>3</sub>A-ligand
stabilizes its target protein. B<sub>3</sub>A ligands stimulate activity
of purified 20S proteasome, demonstrating that the tag binds directly
to the 20S proteasome. Moreover, purified 20S proteasome is sufficient
to degrade target proteins in the presence of their respective B<sub>3</sub>A-linked recognition ligands. These observations suggest a
simple model for B<sub>3</sub>A-mediated degradation wherein the B<sub>3</sub>A tag localizes target proteins directly to the 20S proteasome.
Thus, B<sub>3</sub>A ligands are the first example of a ubiquitin-free
strategy for targeted protein degradation