# Strategies for Post-Translational Control of Protein Expression and Their Applications
## 5 Applications
### Drug Discovery  
Many conventional small-molecule drugs inhibit the function of target proteins by binding to the ligand-binding sites of receptors, catalytic sites of enzymes, or functional interaction sites, thereby exerting pharmacological effects. Proteins without \"inhibitory sites\", such as transcription factors, non-enzymatic proteins, and scaffolding proteins, account for about 80% of the human proteome [78; 79]. Those proteins are \"undruggable\" because they are challenging targets for conventional small-molecule drugs. The PROTAC concept of inducing protein degradation has emerged and has shown potential to overcome the limitations of small-molecule inhibitors [80]. The mechanism of action of PROTAC, which recruits an E3 ligase to the target protein, is based on the simultaneous transient interaction of the target protein with the E3 ligase; PROTAC does not need to inhibit the function of the target protein and is, therefore, effective even for undruggable proteins. Furthermore, PROTAC repeats the dissociation from the target protein after ubiquitination and the binding to the new target protein, which decreases the amount of the target protein over time, thus eliminating the need to maintain high drug concentrations to achieve the desired effect. A recently developed approach to quantitatively detect live-cell kinetic degradation of PROTAC will facilitate the further development, profiling, and improvement of these technologies [81]. Examples of drug discovery directed at target protein degradation are as follows: bromodomain-containing protein 4 (BRD4) is a transcriptional coactivator and a potential therapeutic target in cancer. The [PERSON] and [PERSON] groups,respectively designed BRD4 degraders by linking a small BRD4 inhibitor and a ligand for the E3 ligase cereblon [82; 83]. A recent review provides a comprehensive overview of development of PROTAC and its potential application for cancer therapy [84]. Trials are also underway to apply the PROTAC concept to drug discovery for the therapy of neurodegenerative diseases. A common feature of neurodegenerative diseases, such as [PERSON]'s, Parkinson's, and [PERSON]'s diseases, is the accumulation of abnormal proteins, i.e., tau, \(\alpha\)-synuclein, and mutant huntingtin, respectively, in neurons. These abnormal proteins are cytotoxic, and their accumulation causes cell death. [PERSON] et al. transformed a positron emission tomography tracer that binds to pathological tau for diagnostic use into a degrader of pathological tau by linking it to a pomalidomide recruiting the E3 ligase CRBN [85]. [PERSON] et al. designed and synthesized a peptide-based degrader of \(\alpha\)-synuclein that consists of residues 36-45 of \(\beta\)-synuclein as an \(\alpha\)-synuclein-binding domain, and four amino acids (RRRG) as a proteasome-targeting motif, in conjunction with residues 47-57 of the trans-activating transcriptional activator protein of the human immunodeficiency virus, as a membrane-penetrating motif [86]. [PERSON] and colleagues developed small hybrid molecules consisting of a neurodegenerative disease diagnostic agent, such as thioflavin T, which binds specifically to the cross-\(\beta\)-sheet structure of aggregated proteins, and a ligand for the E3 ligase cIAP1, and showed that it induces the degradation of mHtt aggregates [87].