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Thioredoxin and Glutathione Systems
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Thioredoxin and Glutathione Systems

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 March 2015) | Viewed by 67368

Special Issue Editor

Dr. Angela Calderon

E-Mail Website
Guest Editor
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, 4306B Walker Building, Auburn, AL 36849, USA
Interests: biomedical applications of mass spectrometry; natural products drug discovery for infectious diseases; development of LC-MS based bioassays and analytical methods; LC-MS based metabolomic studies; identification and quantitative analysis of proteins and peptides using LC-MS; qNMR based quantitative analysis; In vitro assessment of stability, metabolism and bioavailability of natural products.
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Special Issue Information

Dear Colleagues,

Thioredoxin and glutathione systems are part of the antioxidant systems present in various organisms, varying from Archea to man. Proteins on the cell surface, or in the extracellular environment, are rich in stabilizing disulfides, reflecting oxidizing conditions. In contrast, the intracellular environment is kept reduced and proteins contain many free sulfhydryl groups; disulfides are rare. The major ubiquitous disulfide reductase, responsible for maintaining proteins in their reduced state, is thioredoxin, which is reduced by electrons from NADPH via thioredoxin reductase. The other major factor generally responsible for the low redox potential and high free SH content within the cells, is glutathione (GSH), present in millimolar concentrations and kept reduced by NADPH and glutathione reductase. GSH-dependent disulfide reductions are catalyzed by glutaredoxins overlapping the functions of thioredoxins, but are uniquely reactive with GSH-mixed disulfides. Thiol ± disulfide exchange reactions via redox active disulfides, are efficient for electron transport, and are involved in the mechanisms of essential enzymes, such as ribonucleotide reductase, which is required to provide deoxyribonucleotides for DNA synthesis. Thiol ± disulfide exchange reactions, which are rapid and readily reversible, are also ideally suited to control protein function via the redox state of structural or catalytic SH groups. Oxidation of a critical SH group will generally lead to a changed biological function.

The present special issue focuses on thioredoxin and glutathione systems as targets for drug discovery. All aspects related to drug discovery based on the thioredoxin and glutathione systems will be covered in this Special Issue. It is, therefore, a pleasure to invite high quality studies, as well as timely review papers, on target validation, development of new screening assays to find enzyme inhibitors of thioredoxin and glutathione systems, screening for inhibitors from natural products and synthetic compounds libraries, lead optimization of inhibitors, design of selective inhibitors, investigations on the pharmacodynamics and pharmacokinetics, as well as structure–activity relationships of natural products and synthetic inhibitors of thioredoxin and glutathione systems and future research perspectives.

Dr. Angela I. Calderón
Guest Editor

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Keywords

  • natural products
  • synthetic compounds
  • cancer
  • infectious diseases
  • diseases related to oxidative stress
  • target validation
  • screening assays
  • structure–activity relationship
  • drug design to improve inhibitor selectivity
  • lead optimization
  • future research perspectives in the systems

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Published Papers (8 papers)

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Research

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704 KiB  
Article
Preliminary LC-MS Based Screening for Inhibitors of Plasmodium falciparum Thioredoxin Reductase (PfTrxR) among a Set of Antimalarials from the Malaria Box
by Neil K. Tiwari, Priscilla J. Reynolds and Angela I. Calderón
Molecules 2016, 21(4), 424; https://doi.org/10.3390/molecules21040424 - 28 Mar 2016
Cited by 11 | Viewed by 5996
Abstract
Plasmodium falciparum thioredoxin reductase (PfTrxR) has been identified as a potential drug target to combat growing antimalarial drug resistance. Medicines for Malaria Venture (MMV) has pre-screened and identified a set of 400 antimalarial compounds called the Malaria Box. From those, we [...] Read more.
Plasmodium falciparum thioredoxin reductase (PfTrxR) has been identified as a potential drug target to combat growing antimalarial drug resistance. Medicines for Malaria Venture (MMV) has pre-screened and identified a set of 400 antimalarial compounds called the Malaria Box. From those, we have evaluated their mechanisms of action through inhibition of PfTrxR and found new active chemical scaffolds. Five compounds with significant PfTrxR inhibitory activity, with IC50 values ranging from 0.9–7.5 µM against the target enzyme, were found out of the Malaria Box. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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1457 KiB  
Article
Inhibition of Tapeworm Thioredoxin and Glutathione Pathways by an Oxadiazole N-Oxide Leads to Reduced Mesocestoides vogae Infection Burden in Mice
by Vivian Pasquet, Hugo Bisio, Gloria V. López, Laura Romanelli-Cedrez, Mariana Bonilla, Jenny Saldaña and Gustavo Salinas
Molecules 2015, 20(7), 11793-11807; https://doi.org/10.3390/molecules200711793 - 26 Jun 2015
Cited by 6 | Viewed by 7041
Abstract
Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising [...] Read more.
Parasitic flatworms cause serious infectious diseases that affect humans and livestock in vast regions of the world, yet there are few effective drugs to treat them. Thioredoxin glutathione reductase (TGR) is an essential enzyme for redox homeostasis in flatworm parasites and a promising pharmacological target. We purified to homogeneity and characterized the TGR from the tapeworm Mesocestoides vogae (syn. M. corti). This purification revealed absence of conventional TR and GR. The glutathione reductase activity of the purified TGR exhibits a hysteretic behavior typical of flatworm TGRs. Consistently, M. vogae genome analysis revealed the presence of a selenocysteine-containing TGR and absence of conventional TR and GR. M. vogae thioredoxin and glutathione reductase activities were inhibited by 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole N2-oxide (VL16E), an oxadiazole N-oxide previously identified as an inhibitor of fluke and tapeworm TGRs. Finally, we show that mice experimentally infected with M. vogae tetrathyridia and treated with either praziquantel, the reference drug for flatworm infections, or VL16E exhibited a 28% reduction of intraperitoneal larvae numbers compared to vehicle treated mice. Our results show that oxadiazole N-oxide is a promising chemotype in vivo and highlights the convenience of M. vogae as a model for rapid assessment of tapeworm infections in vivo. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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4146 KiB  
Article
Glutathione Levels and Susceptibility to Chemically Induced Injury in Two Human Prostate Cancer Cell Lines
by Lawrence H. Lash, David A. Putt and Adam D. Jankovich
Molecules 2015, 20(6), 10399-10414; https://doi.org/10.3390/molecules200610399 - 5 Jun 2015
Cited by 14 | Viewed by 8794
Abstract
More aggressive prostate cancer cells (PCCs) are often resistant to chemotherapy. Differences exist in redox status and mitochondrial metabolism that may help explain this phenomenon. Two human PCC lines, PC-3 cells (more aggressive) and LNCaP cells (less aggressive), were compared with regard to [...] Read more.
More aggressive prostate cancer cells (PCCs) are often resistant to chemotherapy. Differences exist in redox status and mitochondrial metabolism that may help explain this phenomenon. Two human PCC lines, PC-3 cells (more aggressive) and LNCaP cells (less aggressive), were compared with regard to cellular glutathione (GSH) levels, susceptibility to either oxidants or GSH depletors, and expression of several proteins involved in apoptosis and stress response to test the hypothesis that more aggressive PCCs exhibit higher GSH concentrations and are relatively resistant to cytotoxicity. PC-3 cells exhibited 4.2-fold higher GSH concentration than LNCaP cells but only modest differences in acute cytotoxicity were observed at certain time points. However, only LNCaP cells underwent diamide-induced apoptosis. PC-3 cells exhibited higher levels of Bax and caspase-8 cleavage product but lower levels of Bcl-2 than LNCaP cells. However, LNCaP cells exhibited higher expression of Fas receptor (FasR) but also higher levels of several stress response and antioxidant proteins than PC-3 cells. LNCaP cells also exhibited higher levels of several mitochondrial antioxidant systems, suggesting a compensatory response. Thus, significant differences in redox status and expression of proteins involved in apoptosis and stress response may contribute to PCC aggressiveness. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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2994 KiB  
Article
Cysteine Specific Targeting of the Functionally Distinct Peroxiredoxin and Glutaredoxin Proteins by the Investigational Disulfide BNP7787
by Aulma R. Parker, Pavankumar N. Petluru, Vicki L. Nienaber, John Badger, Betsy D. Leverett, Kamwing Jair, Vandana Sridhar, Cheyenne Logan, Philippe Y. Ayala, Harry Kochat and Frederick H. Hausheer
Molecules 2015, 20(3), 4928-4950; https://doi.org/10.3390/molecules20034928 - 18 Mar 2015
Cited by 9 | Viewed by 8111
Abstract
Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the [...] Read more.
Glutaredoxin (Grx), peroxiredoxin (Prx), and thioredoxin (Trx) are redoxin family proteins that catalyze different types of chemical reactions that impact cell growth and survival through functionally distinct intracellular pathways. Much research is focused on understanding the roles of these redoxin proteins in the development and/or progression of human diseases. Grx and Prx are overexpressed in human cancers, including human lung cancers. BNP7787 is a novel investigational agent that has been evaluated in previous clinical studies, including non-small cell lung cancer (NSCLC) studies. Herein, data from activity assays, mass spectrometry analyses, and X-ray crystallographic studies indicate that BNP7787 forms mixed disulfides with select cysteine residues on Grx and Prx and modulates their function. Studies of interactions between BNP7787 and Trx have been conducted and reported separately. Despite the fact that Trx, Grx, and Prx are functionally distinct proteins that impact oxidative stress, cell proliferation and disease processes through different intracellular pathways, BNP7787 can modify each protein and appears to modulate function through mechanisms that are unique to each target protein. Tumor cells are often genomically heterogeneous containing subpopulations of cancer cells that often express different tumor-promoting proteins or that have multiple dysregulated signaling pathways modulating cell proliferation and drug resistance. A multi-targeted agent that simultaneously modulates activity of proteins important in mediating cell proliferation by functionally distinct intracellular pathways could have many potentially useful therapeutic applications. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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Review

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1952 KiB  
Review
Metal- and Semimetal-Containing Inhibitors of Thioredoxin Reductase as Anticancer Agents
by Valentina Gandin and Aristi P. Fernandes
Molecules 2015, 20(7), 12732-12756; https://doi.org/10.3390/molecules200712732 - 14 Jul 2015
Cited by 56 | Viewed by 6941
Abstract
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox homeostasis and signaling pathways. Recently, these selenoproteins have emerged as promising therapeutic targets for anticancer drug development, often being overexpressed in tumor [...] Read more.
The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox homeostasis and signaling pathways. Recently, these selenoproteins have emerged as promising therapeutic targets for anticancer drug development, often being overexpressed in tumor cells and contributing to drug resistance. Herein, we summarize the current knowledge on metal- and semimetal-containing molecules capable of hampering mammalian TrxRs, with an emphasis on compounds reported in the last decade. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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1021 KiB  
Review
Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery
by Sara E. McCarty, Amanda Schellenberger, Douglas C. Goodwin, Ngolui Rene Fuanta, Babu L. Tekwani and Angela I. Calderón
Molecules 2015, 20(6), 11459-11473; https://doi.org/10.3390/molecules200611459 - 22 Jun 2015
Cited by 19 | Viewed by 7557
Abstract
The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed [...] Read more.
The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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831 KiB  
Review
Role and Regulation of Glutathione Metabolism in Plasmodium falciparum
by Sylke Müller
Molecules 2015, 20(6), 10511-10534; https://doi.org/10.3390/molecules200610511 - 8 Jun 2015
Cited by 53 | Viewed by 9294
Abstract
Malaria in humans is caused by one of five species of obligate intracellular protozoan parasites of the genus Plasmodium. P. falciparum causes the most severe disease and is responsible for 600,000 deaths annually, primarily in Sub-Saharan Africa. It has long been suggested that [...] Read more.
Malaria in humans is caused by one of five species of obligate intracellular protozoan parasites of the genus Plasmodium. P. falciparum causes the most severe disease and is responsible for 600,000 deaths annually, primarily in Sub-Saharan Africa. It has long been suggested that during their development, malaria parasites are exposed to environmental and metabolic stresses. One strategy to drug discovery was to increase these stresses by interfering with the parasites’ antioxidant and redox systems, which may be a valuable approach to disease intervention. Plasmodium possesses two redox systems—the thioredoxin and the glutathione system—with overlapping but also distinct functions. Glutathione is the most abundant low molecular weight redox active thiol in the parasites existing primarily in its reduced form representing an excellent thiol redox buffer. This allows for an efficient maintenance of the intracellular reducing environment of the parasite cytoplasm and its organelles. This review will highlight the mechanisms that are responsible for sustaining an adequate concentration of glutathione and maintaining its redox state in Plasmodium. It will provide a summary of the functions of the tripeptide and will discuss the potential of glutathione metabolism for drug discovery against human malaria parasites. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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1366 KiB  
Review
Glutathione in Cellular Redox Homeostasis: Association with the Excitatory Amino Acid Carrier 1 (EAAC1)
by Koji Aoyama and Toshio Nakaki
Molecules 2015, 20(5), 8742-8758; https://doi.org/10.3390/molecules20058742 - 14 May 2015
Cited by 125 | Viewed by 12653
Abstract
Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under [...] Read more.
Reactive oxygen species (ROS) are by-products of the cellular metabolism of oxygen consumption, produced mainly in the mitochondria. ROS are known to be highly reactive ions or free radicals containing oxygen that impair redox homeostasis and cellular functions, leading to cell death. Under physiological conditions, a variety of antioxidant systems scavenge ROS to maintain the intracellular redox homeostasis and normal cellular functions. This review focuses on the antioxidant system’s roles in maintaining redox homeostasis. Especially, glutathione (GSH) is the most important thiol-containing molecule, as it functions as a redox buffer, antioxidant, and enzyme cofactor against oxidative stress. In the brain, dysfunction of GSH synthesis leading to GSH depletion exacerbates oxidative stress, which is linked to a pathogenesis of aging-related neurodegenerative diseases. Excitatory amino acid carrier 1 (EAAC1) plays a pivotal role in neuronal GSH synthesis. The regulatory mechanism of EAAC1 is also discussed. Full article
(This article belongs to the Special Issue Thioredoxin and Glutathione Systems)
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