Abstract
Targeted protein degradation is a promising strategy in therapeutics. Several small molecule approaches have been developed that cause target proteins to be degraded by the 26S proteasome. Such methods include ubiquitination, chaperones, and the 26S proteasome. Our laboratory also discovered that a recognition ligand linked to tert-butyl carbamate-protected arginine (Boc 3Arg, or B3A) induces degradation of a target protein.This thesis details the research into the mechanism of Boc3Arg mediated degradation. This process requires the proteasome but does not involve ubiquitination of the target protein. It is also shown that the Boc3 Arg moiety stimulates the 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 B3A-linked recognition ligands. These observations suggest a simple model for B3A-mediated degradation wherein the B 3A tag localizes target proteins directly to the 20S proteasome. Thus, B3A ligands are the first example of an ubiquitin-free strategy for targeted protein degradation.
Includes bibliographical references.