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Yao, T.;  Xiao, H.;  Wang, H.;  Xu, X. Proteolysis-targeting Chimeras for Drug Targeted Protein Research. Encyclopedia. Available online: https://encyclopedia.pub/entry/27480 (accessed on 25 November 2024).
Yao T,  Xiao H,  Wang H,  Xu X. Proteolysis-targeting Chimeras for Drug Targeted Protein Research. Encyclopedia. Available at: https://encyclopedia.pub/entry/27480. Accessed November 25, 2024.
Yao, Tingting, Heng Xiao, Hong Wang, Xiaowei Xu. "Proteolysis-targeting Chimeras for Drug Targeted Protein Research" Encyclopedia, https://encyclopedia.pub/entry/27480 (accessed November 25, 2024).
Yao, T.,  Xiao, H.,  Wang, H., & Xu, X. (2022, September 22). Proteolysis-targeting Chimeras for Drug Targeted Protein Research. In Encyclopedia. https://encyclopedia.pub/entry/27480
Yao, Tingting, et al. "Proteolysis-targeting Chimeras for Drug Targeted Protein Research." Encyclopedia. Web. 22 September, 2022.
Proteolysis-targeting Chimeras for Drug Targeted Protein Research
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This entry is adapted from the peer-reviewed paper 10.3390/ijms231810328

Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin–proteasome system (UPS).

PROTAC target protein protein degradation

1. Introduction

Targeted protein degradation (TPD) is an emerging therapeutic modality that has the potential to solve the dilemma faced by traditional small molecule targeted therapy. Targeted protein degradation currently mainly degrades target proteins through ubiquitin–proteasome and lysosome. At present, molecular glue and PROTAC technology are the fastest growing in the field of targeted protein degradation [1].
Crews et al. introduced PROTAC for the first time in 2001, and PROTAC works by reducing protein levels rather than inhibiting protein function [2][3][4]. As a bifunctional small molecule compound, typically PROTAC consists of two terminals which are the ligand of the target protein and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker [5][6][7][8][9][10]. PROTAC degrades target proteins through the ubiquitin–proteasome system (UPS). The general process is that PROTAC binds the target protein (POI) and E3 ligase to form a ternary complex, marking the target protein with the label of ubiquitination. The ubiquitinated proteins are recognized and degraded by the intracellular 26S proteasome [11][12][13][14][15][16][17][18][19] (Figure 1). The E3 ubiquitin ligase has approximately more than 600 members and is the most diverse component of the ubiquitin–proteasome system. The E3 ligases reported in the literature currently used in PROTAC mainly include Cereblon E3 ubiquitin ligase complex (CRBN), Von Hippel–Lindau-containing complex (VHL), inhibitor of apoptosis protein (IAP), and mouse double minute 2 (MDM2). The E3 ligases with the best effect and the highest frequency are mainly CRBN and VHL. Among them, the ligands of CRBN are mainly lenalidomide (Figure 2), thalidomide (Figure 2), and their analogs, while the ligands of VHL are mainly VHL-L (Figure 2) and 3-fluoro-VHL ligand [20][21][22][23][24] (Figure 2). PROTAC structurally connects two ligands through the linkers. The composition and length of the linker play an important role in PROTAC. Generally speaking, the composition and length of the linkers have different effects on degradation activity according to different targets. In addition, linked sites of the linkers also affect degradation activity. The binding sites of POI ligands and E3 ligase ligands are generally in the regions where the ligands are exposed to solvents. The connecting sites are generally connected by amide bonds, carbon atoms, or heteroatoms [25].
Figure 1. Mechanism of PROTAC.
Figure 2. Existing E3 ligands used for targeted protein degradation applications.
Compared with traditional therapies, PROTAC technology has advantages such as wider scope of action, higher activity, and targeting “undruggable” targets. First, PROTAC can degrade the entire target protein to affect protein function, which is expected to solve the potential drug resistance problem faced by current traditional therapies; second, in theory, PROTAC can grasp the target protein through any corner and gap; therefore, PROTAC can target “undruggable target“; third, PROTAC can also affect non-enzymatic functions and expand the drug space of the target. So far, PROTACs have been successfully used to degrade several distinct target proteins associated with all kinds of illnesses, such as cancer, immune disorders, neurodegenerative conditions, cardiovascular diseases as well as viral infections [26][27][28]. In particular, 60 successful cases have demonstrated the effectiveness of PROTACs in degrading target proteins, two of which are currently in clinical trials for prostate and breast cancer treatment [29][30]. PROTAC has emerged as a fresh approach to medication development, providing a fresh method of treating disease.

2. Application of PROTAC in Anticancer

Cancer is one of the worst illnesses threatening human health. In recent years, the treatment of cancer is no longer confined to traditional surgery and radiotherapy and chemotherapy. Targeted therapy and immunotherapy play an important role in anti-cancer treatment. However, there are still no effective targeted drugs for “undruggable targets” such as KRAS and TP53 [31]. The ability to shift the target from “no drug” to “drug” is the most main benefit of PROTAC technology. Traditional targeted drugs need to be firmly bound to the target protein. Since PROTAC protein degrading agent can specifically “label” the target protein only by weakly binding with it, PROTAC degradation agent may solve about 80% of the current “undruggable” proteome. It is a timely help for patients who cannot carry out traditional targeted therapy [32].

3. Application of PROTAC in Immune Diseases

Immune inflammatory diseases are very common diseases in life, such as rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and so on. These diseases are threatening people’s health all the time. Scientists’ research on the treatment strategies for these diseases has never stopped. As an emerging strategy, PROTAC has penetrated into the treatment field of immune-inflammatory diseases. The following introduces the use of PROTAC in several applications in immune inflammatory disease targets.

4. Application of PROTAC in Neurodegenerative Diseases

Neurodegenerative diseases are an area in need of new therapies and molecular insights. The aggregation of misfolded proteins such as tau protein and α-synuclein protein is the main cause of such diseases, and they cannot be modulated by traditional small molecule drugs; therefore, the treatment of neurodegenerative diseases has always been a challenge. In recent years, the use of PROTAC technology to degrade target proteins has become a new treatment method. Therefore, PROTAC technology is expected to play a potential role in neurodegenerative diseases caused by protein aggregation.

5. Application of PROTAC in Cardiovascular Diseases

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes 3-hydroxy-3-methylglutaryl coenzyme A in the cholesterol synthesis pathway. HMGCR is a target of statins for the prevention and treatment of cardiovascular diseases [33][34]. In 2020, Luo’s team reported a series of PROTAC molecules [35], among which PROTAC 67 (Table 1) has the greatest impact on the HMGCR protein’s ability to degrade in Chinese hamster ovary SRD15 cells. Additionally, PROTAC 67 activates the sterol regulatory element-binding protein pathway (SREBP) and blocks cholesterol synthesis. That same year, Xiang’s group [36] reported two kinds of lovastatin acid and VHL ligand-conjugated HMGCR targeting PROTAC 68 (Table 1) and 69 (Table 1), and PROTAC 68 could effectively degrade HMGCR in HepG2 cells (DC50 = 120 nM). In vivo studies have shown that PROTAC 69 induces HMGCR breakdown and cholesterol reduction in mice with diet-induced hypercholesterolemia.
Table 1. Representative PROTACs for cardiovascular diseases.
Protac Target Structure Activity Ref.
DC50 Dmax%
67 HMGCR Ijms 23 10328 i068 0.1 μM - [35]
68 Ijms 23 10328 i069 120 nM 76 [36]
69 Ijms 23 10328 i070 - 56 [36]
Note: red: molecule to bind to POI, black: linker, blue: ligand of E3 ligase.

6. Application of PROTAC in Antiviral

Infection with hepatitis C virus (HCV) is the main cause of chronic liver disease, in which the hepatitis C virus (HCV) NS3 protein plays an important role [37][38]. Although VX-950, an inhibitor of the NS3/4A protease, has been authorized for the treatment of HCV, patients are prone to develop drug resistance, so a new treatment method is urgently needed to solve this problem. Yang Priscilla L. et al. synthesized many NS3-targeting PROTACs [39] by linking VX-950 and CRBN Binder based on the PROTAC strategy. Among them, the representative compound PROTAC 70 (Table 2) can effectively degrade NS3 in human hepatoma adherent Huh7.5 cells. In addition, PROTAC 70 can also degrade V55A and A156S mutant NS3. Therefore, the successful discovery of this degradation agent is a boon for HCV-infected patients. This study also suggests that PROTACs may also be potential antiviral drugs, a strategy that has also been used to target SARS-CoV-2 as it emerges. The major proteases (Mpro and PLpro) [40] and RNA-dependent RNA polymerase (RdRP) [41] of SARS-CoV-2 are currently targeted by small molecule inhibitors [42]. They could be potential targets for PROTAC molecules.
Table 2. Representative PROTACs for antiviral.
Indication PROTAC Target Structure Activity Ref.
DC50 Dmax%
HCV 70 NS3 Ijms 23 10328 i071 50 nM - [39]
Note: red: molecule to bind to POI, black: linker, blue: ligand of E3 ligase.

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Subjects: Chemistry, Medicinal
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Tingting Yao
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Heng Xiao
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Xiaowei Xu
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