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Biomedical subjects

Claus Jacob

Publications and source records attributed to Claus Jacob.

At least 19 recordsLinked to original sources
PubMed2006

A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms.

A range of sulfur-containing natural products from plants, fungi, bacteria and animals have recently been investigated to determine their therapeutic potential. Preliminary in vitro and in vivo studies of compounds such as ergothioneine, ovothiols, allicin, leinamycin, varacin, lenthionine and diallyltetrasulfide have provided evidence for antioxidant, antibacterial, antimicrobial, antifungal and anticancer properties. The biological activity of these compounds is the result of specific chemical properties which converge in chemotypes such as thiols, disulfides, sulfenic and sulfinic acids,thiosulfinates, sulfoxides, sulfones and polysulfides. Redox-activity, catalysis, metal binding, enzyme inhibition and radical generation allow reactive sulfur species to interact with oxidative stressors, to affect the function of redox-sensitive cysteine proteins and to disrupt the integrity of DNA and cellular membranes. In some cases, the biological activity of sulfur-containing plant products depends on initial enzymatic activation, which allows thiosulfinates and isothiocyanates to be generated with high target selectivity. Not surprisingly, research into the biochemical and pharmacological properties of the lesser known sulfur chemotypes is rapidly gathering momentum.

Bacteria↗
PubMed2006

Sensor/effector drug design with potential relevance to cancer.

Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their 'healthy' counterparts. Some tumors, such as solid lung carcinoma, are hypoxic, and its cells are therefore more reducing than normal, while others, such as the ones of breast and prostate cancer, proliferate under oxidative stress (OS). These biochemical differences between normal and tumor tissue are significant, and can be used to design effective, yet selective redox drugs. The resulting drug design can follow different avenues. The bioreductive approach is perhaps the most advanced, and uses changes in intracellular redox enzyme concentrations to activate otherwise inactive pro-drug molecules inside cancer cells by a reductive step, often followed by further chemical transformations, such as hydrolysis. Related anti-cancer compounds, such as varacin, employ an intricate combination of reduction and oxidation processes to develop their therapeutic potential inside cells. Another, just emerging approach considers the use of pro-oxidants and catalysts, taking advantage of the inherent efficiency and selectivity associated with OS-induced cell death. Even more complex tactics, such as chelator-assisted photodynamic therapy, exploit the intracellular metal homeostasis to target cancer cells. Together, all of these avenues try to endow molecules with a combination of sensor and effector properties, which might allow them to single out and selectively kill cancer cells without the need for cell-selective drug delivery systems. In the long term, such agents could be associated with high efficiency, good selectivity and dramatically reduced drug side effects.

Animals↗
PubMed2005

Multifunctional redox catalysts as selective enhancers of oxidative stress.

Certain cancer cells proliferate under conditions of oxidative stress (OS) and might therefore be selectively targeted by redox catalysts. Among these catalysts, compounds containing a chalcogen and a quinone redox centre are particularly well suited to respond to the presence of OS. These catalysts combine the specific electrochemical features of quinones and chalcogens. They exhibit high selectivity and efficiency against oxidatively stressed rat PC12, human Jurkat and human Daudi cells in cell culture, where their mode of action most likely involves the catalytic activation of existent and the generation of new reactive oxygen species. The high efficiency and selectivity shown by these catalysts makes them interesting for the development of anti-cancer drugs.

Animals↗
PubMed2005

Towards multifunctional antioxidants: synthesis, electrochemistry, in vitro and cell culture evaluation of compounds with ligand/catalytic properties.

Numerous human diseases are linked to a biochemical condition known as oxidative stress (OS). Antioxidants are therefore becoming increasingly important as potential disease prevention and therapeutic agents. Since OS is a multi-stressor event, agents combining a range of different antioxidant properties, such as redox catalysis and metal binding, might be more effective and selective than mono-functional agents. Selenium derivatives of aniline and pyridine combine redox activity with metal binding properties. These multifunctional agents have a distinct electrochemical profile, and exhibit good catalytic activity in the glutathione peroxidase mimic and metallothionein assays. They also show antioxidant activity in a skin cell model of UVA-induced stress. These compounds might therefore provide the basis for novel agents combining two or more distinct antioxidant properties.

Antioxidants↗
PubMed2005

Use of a substrate/alliinase combination to generate antifungal activity in situ.

Allicin, an active ingredient of garlic, possesses a range of antimicrobial properties. Unfortunately, certain properties of the compound, such as chemical instability and low miscibility with water, have hampered its practical use in the past. Here, we show that it is possible to use a binary system consisting of the plant enzyme alliinase and its substrate alliin to generate allicin, and hence antifungal activity, in situ. During application, the two inactive components generate compounds that inhibit growth and infection-related development of the rice blast fungus Magnaporthe grisea. It is therefore possible to "trigger" biological activity in a controlled, yet effective manner. Apart from circumventing many of the drawbacks of allicin, this binary system has additional important advantages, such as low toxicity of its individual components and selective activation. Importantly, alliinase is also able to use different substrates, therefore paving the way to a range of novel, binary antimicrobial systems with custom-made chemical and biochemical properties.

Carbon-Sulfur Lyases↗
PubMed2005

Oxidative activation of antioxidant defence.

Living cells maintain a delicate balance between oxidizing and reducing species, and many disorders such as rheumatoid arthritis and Alzheimer's disease have been associated with a disturbed intracellular 'redox equilibrium'. The past few years have witnessed accelerated research into how natural redox responses and antioxidant defence systems are activated and how they restore a healthy redox balance. To function properly, many of these processes rely on a powerful sulfur redox chemistry, which is best exemplified by the complex, newly emerging cysteine-based redox regulation of the glutathione and thioredoxin pathways. Other redox systems based on oxidatively activated amino acid side chains in proteins are also becoming increasingly important, but are still barely understood or explored.

Animals↗
PubMed2004

The sulfinic acid switch in proteins.

Recent studies on the redox behaviour of cysteine residues in peptides and proteins have dramatically changed our perspective of the amino acid's role in biocatalysis, intracellular redox sensing and cell signalling. Cysteine sulfinic acid formation in proteins, for example, has long been viewed as an irreversible 'overoxidation' process that might lead to loss of activity, especially under conditions of oxidative stress. Within the last year, several research groups have independently shown that sulfinic acids can be reduced to thiols in vivo. An enzyme with sulfinic acid reductase activity, called sulfiredoxin, has been isolated from yeast and a gene encoding a human analogue has been identified in the human genome. Reversibility of sulfinic acid formation opens the door to a range of yet unexplored redox cycles, cell signalling processes and reduction mechanisms. These cysteine-based redox processes will be of enormous interest to chemists, biochemists, biologists and the medical community alike.

Catalysis↗
PubMed2004

A fungal metallothionein is required for pathogenicity of Magnaporthe grisea.

The causal agent of rice blast disease, the ascomycete fungus Magnaporthe grisea, infects rice (Oryza sativa) plants by means of specialized infection structures called appressoria, which are formed on the leaf surface and mechanically rupture the cuticle. We have identified a gene, Magnaporthe metallothionein 1 (MMT1), which is highly expressed throughout growth and development by M. grisea and encodes an unusual 22-amino acid metallothionein-like protein containing only six Cys residues. The MMT1-encoded protein shows a very high affinity for zinc and can act as a powerful antioxidant. Targeted gene disruption of MMT1 produced mutants that show accelerated hyphal growth rates and poor sporulation but had no effect on metal tolerance. Mmt1 mutants are incapable of causing plant disease because of an inability to bring about appressorium-mediated cuticle penetration. Mmt1 appears to be distributed in the inner side of the cell wall of the fungus. These findings indicate that Mmt1-like metallothioneins may play a novel role in fungal cell wall biochemistry that is required for fungal virulence.

Amino Acid Sequence↗
PubMed2003

Targeting oxidative stress-related diseases: organochalcogen catalysts as redox sensitizers.

Tumor cells proliferate under conditions of oxidative stress. A novel therapeutic approach would be to enhance the cellular effects of the reactive oxygen species formed under these conditions by supplementation with a redox catalyst. This provides a means to target and specifically destroy cancer cells via oxidation of redox-sensitive proteins, such as transcription factors, while leaving cells with a normal redox balance largely unaffected. We have previously reported a preliminary observation on the effects of pro-oxidant catalysts that enhance cancer cell death. This paper presents a detailed in vitro investigation into the mechanism of action of synthetic glutathione peroxidase mimics on a model Sp1 transcription factor peptide. The structure and redox potential of these mimics correlate with their ability to catalyze the oxidation of this zinc-binding motif by H(2)O(2) and these compounds promise therapeutic potential by promoting H(2)O(2)-induced PC12 cell death.

Animals↗
PubMed2003

Evaluation of sulfur, selenium and tellurium catalysts with antioxidant potential.

Oxidative stress is implicated, either directly or indirectly, in the pathology of a range of human diseases. As a consequence, the development of efficient antioxidants for medical use has become increasingly important. We have synthesised a range of structurally related organo-sulfur, -selenium and -tellurium agents and demonstrated that a combination of electrochemical methodology, in vitro assays and cell culture tests can be used to rationalise the antioxidant activity of these catalytic agents. Based on its exceptionally low anodic oxidation potential (Epa) and high activity against the representative oxidative stressors tert-butyl hydroperoxide and peroxynitrite, 4,4'-dihydroxydiphenyltelluride is predicted to be a potent antioxidant. This compound exhibits a correspondingly high activity with a remarkably low IC50 value of 20 nM, when tested in PC12 cell culture using a bioassay indicative of the early stages of Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Sulfur and selenium: the role of oxidation state in protein structure and function.

Sulfur and selenium occur in proteins as constituents of the amino acids cysteine, methionine, selenocysteine, and selenomethionine. Recent research underscores that these amino acids are truly exceptional. Their redox activity under physiological conditions allows an amazing variety of posttranslational protein modifications, metal free redox pathways, and unusual chalcogen redox states that increasingly attract the attention of biological chemists. Unlike any other amino acid, the "redox chameleon" cysteine can participate in several distinct redox pathways, including exchange and radical reactions, as well as atom-, electron-, and hydride-transfer reactions. It occurs in various oxidation states in the human body, each of which exhibits distinctive chemical properties (e.g. redox activity, metal binding) and biological activity. The position of selenium in the periodic table between the metals and the nonmetals makes selenoproteins ideal catalysts for many biological redox transformations. It is therefore apparent that the chalcogen amino acids cysteine, methionine, selenocysteine, and selenomethionine exhibit a unique biological chemistry that is the source of exciting research opportunities.

Cysteine↗
PubMed2003

Redox catalysts as sensitisers towards oxidative stress.

The predominance of oxidative stress in many tumour cell environments provides a means to selectively target these cells via protein oxidation. The zinc fingers of transcription factors utilise cysteine thiols for structural zinc coordination. Redox control of DNA binding regulates transcription and therefore the overall rates of proliferation, apoptosis and necrosis in the carcinoma. We report here the adverse effects of glutathione peroxidase (GPx) mimics towards zinc finger motifs and PC12 cell survival. Nanomolar catalyst concentrations facilitated H2O2-induced oxidation of an Sp1 transcription factor fragment. In PC12 cells GPx catalysis triggered a significant increase in cell death, correlating with severity of oxidative stress. As a consequence, we conclude that GPx mimics are potential chemotherapeutic agents.

Animals↗
PubMed2003

Multiple roles of cysteine in biocatalysis.

In biology, sulfur frequently occurs in the form of cysteine, an amino acid that fulfills a wide range of different functions in proteins including disulfide formation, metal-binding, electron donation, hydrolysis, and redox-catalysis. The 'redox-chameleon' sulfur appears in several oxidation states in vitro, each of them exhibiting specific reactivity, redox-activity, and metal-binding properties. While cysteine-peptidases rely on reduced cysteine to catalyze hydrolytic reactions, many redox-enzymes use distinctively different cysteine redox-couples for exchange, electron, atom, and radical transfer reactions. Although cysteine and cystine can still be considered as the most abundant forms of cysteine in vivo, other modifications such as cysteine acids and sulfur-centered radicals are becoming increasingly important in biochemical research. As such, the biochemistry of sulfur remains a source of continuous investigation and excitement.

Catalysis↗
PubMed2003

Metal and redox modulation of cysteine protein function.

In biological systems, the amino acid cysteine combines catalytic activity with an extensive redox chemistry and unique metal binding properties. The interdependency of these three aspects of the thiol group permits the redox regulation of proteins and metal binding, metal control of redox activity, and ligand control of metal-based enzyme catalysis. Cysteine proteins are therefore able to act as "redox switches," to sense concentrations of oxidative stressors and unbound zinc ions in the cytosol, to provide a "storage facility" for excess metal ions, to control the activity of metalloproteins, and to take part in important regulatory and signaling pathways. The diversity of cysteine's multiple roles in vivo is equally as fascinating as it is promising for future biochemical and pharmacological research.

Catalysis↗
PubMed2003

Statement analysis in chemistry.

Close philosophical examination of chemical research reports ("statement analysis") can lead to clarification of ambiguities and resolution of logical confusions, and also lead to other useful conclusions.

Journal Article↗
PubMed2002

Reactive sulphur species: an in vitro investigation of the oxidation properties of disulphide S-oxides.

We have recently proposed that disulphide S-monoxides (thiosulphinates) and disulphide S-dioxides (thiosulphonates) are formed from their parent disulphides and 'reactive oxygen species' during oxidative stress. These 'reactive sulphur species' are themselves strong oxidizing agents that preferably attack the thiol functionality. We now show that under conditions where disulphides show little effect, disulphide S-oxides rapidly modify metallothionein, alcohol and glyceraldehyde 3-phosphate dehydrogenases and a zinc finger-protein fragment in vitro. The known antioxidants ascorbate, NADH, trolox and melatonin are unable to inhibit this oxidation pathway and only an excess of the cellular redox-buffer glutathione quenches the disulphide S-oxide activity. These results suggest that, under conditions of oxidative stress, despite the presence of high concentrations of antioxidants, reactive sulphur species formation may occur and inhibit the function of thiol-dependent proteins. Such a characterization of the disulphide S-oxide-oxidation pathway might also account for some previously observed anomalies in protein oxidation.

Antioxidants↗