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Extrahepatic Synthesis of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Gerhard Schreiber, Angela R. Aldred
Regulatory changes in the rates of synthesis of extracellular proteins are observed when protein homeostasis is challenged. Changes in the rates of incorporation of radioactive amino acids into plasma proteins usually reflect changes in the levels of mRNAs, indicating that translational or posttranslational control of protein synthesis is of no, or minor, importance.118 Alteration of the transcriptional activity of the genes is the major mechanism leading to changes in mRNA levels, but in some cases, changes in the stability of mRNAs also play a role.119 The challenges to extracellular homeostasis differ in the various extracellular compartments of the body. Thus, it is not surprising that regulation of the expression of the transthyretin gene in choroid plexus is independent of that in liver68 (Table 3).
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
The proteostasis network includes cellular pathways that together maintain protein homeostasis by regulating protein synthesis, folding, trafficking, and degrading, and as such it is an attractive target for the development of therapeutic approaches (125). S-nitrosation (or S-nitrosylation) is a cellular post-translational modification by which nitric oxide (NO) is transferred to a protein thiol group and thereby regulates NO-mediated signaling pathways. The S-nitrosoglutathione reductase (GSNOR) alcohol dehydrogenase (ADH) enzyme is responsible for metabolizing S-nitrosoglutathione (GSNO), which is the main source of nitric oxide in cells, and as such regulates NO levels for protein S-nitrosation (126).
Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Proteostasis or protein homeostasis is the equilibrium state between protein synthesis and degradation. Proteostasis is a fundamental mechanism to maintain cellular and organismal wellbeing. Previous studies demonstrate that aging and age-dependent degenerative diseases are associated with abnormal accumulation of defective proteins and biomolecules as a result of oxidative damage and inefficient removal of damaged proteins.31 Examples of such proteins include neurofibrillary tangles (NFTs) and beta amyloid proteins in Alzheimer's disease (AD), alpha synuclein in Parkinson's disease (PD),32 lipofuscin and senile amyloid in cardiac and skeletal muscle ageing,33,34–36 and damaged crystallins in cataracts.37 The defective proteostasis has been observed prior to development of various degenerative diseases,38 emphasizing critical roles of maintaining protein quality control.
Thermodynamic and kinetic approaches for drug discovery to target protein misfolding and aggregation
Published in Expert Opinion on Drug Discovery, 2023
Therapeutic interventions could thus be aimed at supplementing the protein homeostasis system as it is progressively impaired upon aging. In broad terms, one could think of two complementary strategies to reduce the driving force toward aggregation, the first based on the thermodynamics and the second on the kinetics of the process (Figure 1). In a thermodynamic strategy, since supersaturation depends on the free energy difference between the native and amyloid states, the aim is to develop compounds that stabilize native states [16,28–32]. In a kinetic strategy, the goal is to increase the height of the free energy barrier between the native and amyloid states. In this second approach, the thermodynamic driving force remains unchanged, but the process is slowed down, so that even a protein homeostasis system of reduced functionality could effectively remove the aggregates [33–38]. We should point out that the optimization of the kinetics of binding of small molecules to their targets, in terms of the balance between on rates and off rates, has a long history in drug discovery [50–52]. However, the type of kinetic strategy that we are concerned with here is specifically aimed at increasing the rate of conversion of native states into aggregates.
RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease
Published in Expert Opinion on Investigational Drugs, 2023
Pavel Strnad, Javier San Martin
To maintain protein homeostasis, cells have built-in pathways that ensure the fidelity of protein synthesis and folding and that misfolded proteins are properly cleared. In normal cellular physiology, misfolded proteins are typically cleared by the endoplasmic reticulum (ER)-associated protein degradation (ERAD), and the disposal is supported by the unfolded protein response (UPR), two key homeostatic machineries in the cell [1,3–5]. ERAD is responsible for the translocation of misfolded proteins from the ER into the cytoplasm, and their ubiquitination and proteasomal degradation. UPR, a conserved cellular mechanism induced by cellular/ER stress, is activated in response to the accumulation of misfolded proteins and reduces their load to maintain cell viability [6]. As another line of defense, aggregated proteins are targeted for degradation by autophagy, which leads to lysosome-mediated degradation of cytoplasmic contents and organelles. Liver diseases characterized by intracellular protein aggregates often arise when there is an imbalance between production of the misfolded protein and the ability of these endogenous pathways to clear it.
Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Man Yang, Chenyao Li, Yajing Li, Chen Cheng, Meiyun Shi, Lei Yin, Hongyu Xue, Yajun Liu
Because proteins play roles in nearly every cellular process, it is essential to maintain protein homeostasis to preserve normal cell functions. Molecular chaperones are a large family of proteins that guard cellular protein homeostasis by regulating the conformation and quality of client proteins1,2. Heat shock protein 90 (HSP90) is one of the most crucial molecular chaperones in eukaryotes and stabilises and activates more than 400 client proteins3,4. Because cancer cells require higher levels of proteins for survival than normal cells, HSP90 is overexpressed in cancer cells, accounting for 4–6% of the whole proteome5,6. In addition, conformations of normal HSP90 and HSP90 of the cancer phenotype are different, and the latter is more susceptible to inhibitors7. Inhibition of HSP90 in cancer cells results in the degradation of client oncoproteins via the ubiquitin-proteasome pathway and the subsequent disruption of multiple signal transduction pathways, further leading to the apoptosis of cancer cells8,9. Therefore, HSP90 is a promising therapeutic target for discovering anticancer drugs10. Beyond cancer, HSP90 has also emerged as a potential drug target in other protein-related diseases, such as neurodegenerative diseases, infectious diseases, and ageing11–14.