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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The PROTAC approach, initially described by Sakamoto, Crews, and Deshaies in 2001, is an acronym for proteolysis targeting chimera. The technology is based on a heterobifunctional small molecule composed of two active domains joined by a linker (Figure 5.89). Rather than working as a conventional inhibitor, a PROTAC works by inducing selective intracellular proteolysis. The heterobifunctional small molecule consists of two covalently linked protein-binding molecules, one capable of binding to the target transcription factor protein designated for degradation and the other designed to engage E3 ubiquitin ligases such as pVHL, Mdm2, beta-TrCP1, cereblon, and c-IAP1. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation by the 26S proteasome. As this does not block the binding site of the transcription factor, a high concentration of the PROTAC agent is not required to maintain its therapeutic effect, thus minimalizing toxicity and drug resistance. Another advantage of PROTAC is that it can target proteins which do not have enzymatic activities such as scaffolding proteins. However, one potential problem is the narrow E3 library available.
Cell structure, function and adaptation
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
The half-life of cellular proteins varies from seconds to months or years. The haemoglobin protein in red blood cells lasts for more than 100 days before the cell is removed from the circulation. The regulation of cellular proteins is a complex and important process for cell viability and function. If damaged protein accumulates it may inhibit normal protein function or injure the cell directly. Genetic abnormalities resulting in abnormal proteins are implicated in many diseases. In cystic fibrosis (see Chapter 8) a transmembrane chloride channel is dysfunctional, and this results in abnormal mucus secretion that leads to the phenotype seen clinically. In storage diseases, such as α1-antitrypsin disease, an abnormal protein is produced that cannot be efficiently secreted from the cell. The protein accumulates and can cause damage to the liver cells resulting in hepatitis, which may progress to cirrhosis (see Chapter 11). In addition, the absence of functional anti-protease in plasma leads to an increased risk of emphysema developing in the lungs (see Chapter 8). Mutation of tumour-suppressor genes can result in the formation of proteins with abnormal folding characteristics. Sometimes these inhibit the function of the corresponding normal protein (a dominant negative effect) and so contribute to the pathogenesis of cancer (see Chapter 6). Normally, damaged protein is marked for degradation by being bound to a carrier protein called ubiquitin, a process known as ubiquitination. This ubiquitinated protein is then removed from the cellular pool and degraded in the proteasome.
Proteasome and Protease Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
N. E. Franke, J. Vink, J. Cloos, Gertjan J. L. Kaspers
More than 80% of all eukaryotic protein degradation is controlled by the ubiquitin-proteasome pathway (23). This pathway regulates protein ubiquitination, and subsequent recognition and degradation by the proteasome (Fig. 1).
PTK2 regulates tau-induced neurotoxicity via phosphorylation of p62 at Ser403
Published in Journal of Neurogenetics, 2023
Shinrye Lee, Myungjin Jo, Younghwi Kwon, Yu-Mi Jeon, Seyeon Kim, Kea Joo Lee, Hyung-Jun Kim
The ubiquitin–proteasome system (UPS) is a major intracellular protein degradation systems (Nalepa, Rolfe, & Harper, 2006). Ubiquitination-dependent degradation is involved in several cellular processes, such as protein quality control, transcription, DNA repair, the cellular stress response, and apoptosis. Previous studies have revealed that dysfunction of the UPS is associated with many neurological disorders, including AD, amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) (Durcan et al.,2011; Liu, Fallon, Lashuel, Liu, & Lansbury, 2002; Zhang et al.,2012). The UPS impairment in these diseases may be related to defective clearance of misfolded and aggregated proteins, leading to cell death. A recent study also found that the tauopathy in AD is associated with impaired proteolysis mediated by the UPS (Myeku et al.,2016; Tai et al.,2012). However, studies about the molecular mechanisms linking UPS impairment and tauopathies are insufficient.
A patent review of MALT1 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Isabel Hamp, Thomas J. O’Neill, Oliver Plettenburg, Daniel Krappmann
In a fourth application filed by Cornell University (WO2018/085247) [101], an orthogonal approach is disclosed. The patent describes the first proteolysis inducing chimeras (PROTACs) based on urea-containing compounds described above. The PROTAC concept, pioneered by the Crews lab and others [102], utilizes dimeric molecules containing a reversible binder to the protein of interest, as well as an E3 ligase binding moiety. Bringing the ligase and the protein of interest into spatial proximity can result in poly-ubiquitination of said protein, which would render it susceptible to proteolytic degradation. The outer claims are rather broad, with all examples containing pyrazolopyrimidine urea derivatives as described in the Novartis series (Figure 6). Conjugation to the E3 ligase ligand (cereblon binders like thalidomide or pomalidomide) is achieved via the eastern pyridine substituent or via R2. The described degradation potency is rather modest (maximal activity given: >50% degradation at ~1 µM concentration, for compound 46 and 47 (Figure 10)). In contrast to previous series followed up by Cornell University, no manuscript describing cellular effects of these MALT1 degraders has yet been published, making it difficult to judge the general utility of the approach. Nevertheless, complete MALT1 depletion instead of selective protease inhibition is a new strategy, which may provide additional benefits with respect to balancing the immune response with MALT1 inhibitors.
Targeting the TGF-β signaling pathway for fibrosis therapy: a patent review (2015–2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Xuanyi Li, Ziang Ding, Zixuan Wu, Yinqiu Xu, Hequan Yao, Kejiang Lin
Park et al. from Catholic University of Daegu designed a novel synthetic oligodeoxynucleotide (ODN) to simultaneously inhibit DNA and RNA (Table 6). The ODNs contain antisense ODN targeting TGF-β1 and decoy ODN targeting SMAD, which inhibits the transcription of TGF-β1 mRNA and SMAD related genes [94]. Decoy ODN binds to transcription factors in cells, preventing it from binding to the corresponding promoter and reducing the activity of SMAD. Wang et al. from SYSU constructed a proteolysis targeting chimeras (PROTAC) targeting ubiquitination proteins, which collected target proteins to the E3 ligase (Table 6). After ubiquitination, the target protein was degraded through the proteasome pathway. The PROTAC published in the document adopts a double target design, and the target proteins are SMAD3 and HIF-α. The latter is used as an E3 recognition ligand, and specific E3 can be selected to avoid common off target effects of these drugs to improve safety [95].