*10.3. Inhibitor of Ubiquitin*

Many studies have reported the development of novel inhibitors to target druggable enzymes of the UPS. However, the most important molecule, ubiquitin, has not ye<sup>t</sup> been targeted. Recently, Nguyen et al. discovered a compound, Congo red, with the ability to bind to the recognition site and disrupt the binding activity of ubiquitin, thus making it unavailable for ubiquitination. Congo red inhibits the conjugation of K48- and K63-linked polyubiquitination. Inhibiting the ubiquitin itself inhibits all ubiquitin-mediated proteasomal/autophagic degradation, and it can therefore be used to enrich the population of all functional mutant proteins in a cell [135]. The ubiquitin inhibitor, Congo red, by itself or in combination with another strategy, could be important in supporting the survival of functional but misfolded PAH and FAH proteins.

**Figure 2.** Mechanism of proteolysis-targeting chimera (PROTAC) and "Modified" PROTAC. (**A**) Proteolysis-targeting chimaera (PROTAC) are bifunctional molecules, whose one end binds to the protein of interest (POI) while the other recruits E3 ligase forming a ternary complex. The E3 ligase induces proximity-induced ubiquitination of POI by transferring the ubiquitin (Ub) molecules from E2 enzyme to the POI, thus facilitating its degradation; (**B**) Representation of a hypothetical figure where technology can be modified to rescue the functional misfolded proteins undergoing rapid degradation in inherited metabolic disorders like PKU and HT1 having partial functions, causing deficiency of available protein for cellular functions. Hence, a PROTAC can be designed whose one end binds to the misfolded POI and the other binds to a ligand that can recruit the regulatory DUB. The DUBs will cleave off the ubiquitin molecule, avoiding the protein degradation, and will help to maintain a pool of protein required fornormalcellularfunction.
