# Strategies for Post-Translational Control of Protein Expression and Their Applications
## 3 Targeted Protein Degradation Using Bifunctional Molecules or Antibodies
### Protac  
A pioneering work on the targeted protein degradation is the recruitment of the target protein to specific E3 Ub ligases using bifunctional molecules. As a proof-of-concept, the [PERSON] group developed a proteolysis-targeting chimeric molecule (PROTAC) consisting of specific ligands for a protein of interest (POI) and an E3 Ub ligase, with a linker connecting them (Figure 2a) [21]. PROTAC binds to both the POI and an E3 Ub ligase, resulting in the ubiquitination, and degradation of the POI. Those authors synthesized a chimeric large molecule called Protac-1 that recruits an E3 Ub ligase complex, Skp1-CullinF-box (SCF), to a target protein, methionine aminopeptidase-2 (MetAP-2), resulting in its ubiquitination, and degradation. They further developed an all-small-molecule and cell-permeable PROTAC that consists of a ligand for the non-steroidal androgen receptor and a ligand for the E3 Ub ligase MDM2, connected by a polyethylene glycol (PEG)-based linker (Figure 2a) [22]. [PERSON] et al. developed another chimeric molecule called specific and non-genetic IAP-dependent protein eraser (SNIPER), which recruits inhibitor of the apoptosis protein (IAP) Ub ligases to specifically degrade target proteins [23].  
Figure 2: Targeted protein degradation using molecules or antibodies. Concepts of (**a**) PROTAC/SNIPER, (**b**) TRIM-away, (**c**) AUTAC, and (**d**) LYTAC.  
Such chimeric molecules require significant linker optimization and have a high molecular weight of 900-1100 Da, which limits cellular permeability and solubility. [PERSON]'s group reported solution conformations of a von Hippel-Lindau (VHL) E3 Ub ligase-recruiting PROTAC that has a flexible, PEG-based linker [24]. This molecule exhibits an elongated conformation in a polar environment while the conformation is folded in an apolar environment. The folded conformation minimizes the size and polarity, allowing it to permeate the cell membrane. Furthermore, a new approach to solve the problem regarding molecular weight of PROTACs has also emerged. [PERSON] et al. addressed this by using the bio-orthogonal reaction between two smaller precursors of chimeric molecule, which can occur intracellularly [25]. They designed a tetrazine-tagged ligand for an E3 Ub ligase that reacts rapidly with a _trans_-cyclo-octene-tagged ligand for POI in cells, to form an E3 Ub ligase and recruit PROTAC molecule: termed click-formed proteolysis targeting chimera (CLIPTAC). Recent studies achieved another important improvement of PROTAC using optochemistry technologies. [PERSON] et al. developed a light-inducible switch on PROTACs, termed opto-PROTAC by decorating the ligand moiety for E3 ligase with a photolabile caging group [26]. This caged compound shows no activity in the dark, whereas restricted degradation can be induced at a specific time and rate after uncaging of photolabile group by light irradiation. [PERSON] et al. also developed photochemically targeting chimeras (PHOTACs) by introducing azobenzene moieties between ligands for the E3 Ub ligase and the POI [27]. Light irradiation causes the photoreversible isomerization of the azobenzene moiety and switches the active state to induce protein degradation activity. These technologies are useful for application in clinical settings because the spatiotemporal regulation afforded by them avoids the uncontrolled degradation that causes systemic toxicity.