Identification and Characterization of Novel Human Glucose-6-Phosphate Dehydrogenase Inhibitors

Preuss, Janina; Richardson, Adam D.; Pinkerton, Anthony B.; Hedrick, Michael; Sergienko, Eduard; Rahlfs, Stefan; Becker, Katja; Bode, Lars

doi:10.1177/1087057112462131

Cited by 53 publications

(43 citation statements)

References 29 publications

(56 reference statements)

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“…37 These inhibitors, however, have a low efficacy (IC 50 40.4 and 3 mmol/L, respectively) and limited solubility in ACSF, factors that made the use of 6-aminonicotinamide impossible in our experiments. Conversely, dehydroepiandrosterone at 0.3 mmol/L concentration induced strong hyperexcitability manifested by drastic increase in field responses and emergence of interictal spontaneous activity (Supplementary Figure S2), effects that may be explained by its multi-faceted and unspecific activity (e.g., inhibition of GABA A receptors 38 or increase in spontaneous glutamate release 39 ).…”

Section: Replacement Of Glucose With Mitochondrial Energy Substrates mentioning

confidence: 97%

Reactive Oxygen Species Initiate a Metabolic Collapse in Hippocampal Slices: Potential Trigger of Cortical Spreading Depression

Malkov

Ivanov

Popova

et al. 2014

J Cereb Blood Flow Metab

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Excessive accumulation of reactive oxygen species (ROS) underlies oxidative damage. We find that in hippocampal slices, decreased activity of glucose-based antioxidant system induces a massive, abrupt, and detrimental change in cellular functions. We call this phenomenon metabolic collapse (MC). This collapse manifested in long-lasting silencing of synaptic transmission, abnormal oxidation of NAD(P)H and FADH 2 associated with immense oxygen consumption, and massive neuronal depolarization. MC occurred without any preceding deficiency in neuronal energy supply or disturbances of ionic homeostasis and spread throughout the hippocampus. It was associated with a preceding accumulation of ROS and was largely prevented by application of an efficient antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). The consequences of MC resemble cortical spreading depression (CSD), a wave of neuronal depolarization that occurs in migraine, brain trauma, and stroke, the cellular initiation mechanisms of which are poorly understood. We suggest that ROS accumulation might also be the primary trigger of CSD. Indeed, we found that Tempol strongly reduced occurrence of CSD in vivo, suggesting that ROS accumulation may be a key mechanism of CSD initiation.

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Section: Replacement Of Glucose With Mitochondrial Energy Substrates mentioning

confidence: 97%

Reactive Oxygen Species Initiate a Metabolic Collapse in Hippocampal Slices: Potential Trigger of Cortical Spreading Depression

Malkov

Ivanov

Popova

et al. 2014

J Cereb Blood Flow Metab

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“…The results achieved are shown in table 2. shown that this key metabolic enzyme which catalyzes the first step of pentose phosphate pathway is expressed abundantly and very active in human tumors [21]. In contrast, G6PD-deficient tumor cell lines showed relatively slow growth and enhanced apoptosis [41].…”

Section: Resultsmentioning

confidence: 99%

“…G6PD activity increases in cancer cells and its inhibition results in decrease of cell proliferation and induction of apoptosis. For example, 6-aminonicotinamide which is an inhibitor of G6PD has found use in the therapy of various tumors in the past [21].…”

Section: Introductionmentioning

confidence: 99%

Compounds from <em>Terminalia mantaly</em> L. (Combretaceae) Stem Bark Exhibit Potent Inhibition against some Pathogenic Yeasts and Enzymes of Metabolic Significance<strong></strong>

Tchuenmogne

Ngouana

Gohlke

et al. 2016

Preprint

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“…Recently, novel inhibitors of the human G6PDH 23 and of the bifunctional glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase from Plasmodium falciparum (PfGluPho) 24 were identified by HTS. However, no uncompetitive inhibitors were reported from those experiments.…”

Section: Resultsmentioning

confidence: 99%

“…1A). [23][24][25][26][27] The primary screening assay resulted in the identification of 96 hit candidates, which diminished the enzyme activity to at least 62.5%, which is equivalent to the mean percentage of enzyme activity less 5 standard deviations (Fig. 1B).…”

Section: Primary Screeningmentioning

confidence: 99%

Discovery of New Uncompetitive Inhibitors of Glucose-6-Phosphate Dehydrogenase

2014

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The enzyme glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the oxidative branch of the pentose phosphate pathway, which provides cells with NADPH, an essential cofactor for many biosynthetic pathways and antioxidizing enzymes. In Trypanosoma cruzi, the G6PDH has being pursued as a relevant target for the development of new drugs against Chagas disease. At present, the best characterized inhibitors of T. cruzi G6PDH are steroidal halogenated compounds derivatives from the mammalian hormone precursor dehydroepiandrosterone, which indeed are also good inhibitors of the human homologue enzyme. The lack of target selectivity might result in hemolytic side effects due to partial inhibition of human G6PDH in red blood cells. Moreover, the treatment of Chagas patients with steroidal drugs might also cause undesired androgenic side effects. Aiming to identify of new chemical classes of T. cruzi G6PDH inhibitors, we performed a target-based high-throughput screen campaign against a commercial library of diverse compounds. Novel TcG6PDH inhibitors were identified among thienopyrimidine and quinazolinone derivatives. Preliminary structure activity relationships for the identified hits are presented, including structural features that contribute for selectivity toward the parasite enzyme. Our results indicate that quinazolinones are promising hits that should be considered for further optimization.

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Identification and Characterization of Novel Human Glucose-6-Phosphate Dehydrogenase Inhibitors

Cited by 53 publications

References 29 publications

Reactive Oxygen Species Initiate a Metabolic Collapse in Hippocampal Slices: Potential Trigger of Cortical Spreading Depression

Reactive Oxygen Species Initiate a Metabolic Collapse in Hippocampal Slices: Potential Trigger of Cortical Spreading Depression

Compounds from <em>Terminalia mantaly</em> L. (Combretaceae) Stem Bark Exhibit Potent Inhibition against some Pathogenic Yeasts and Enzymes of Metabolic Significance<strong></strong>

Discovery of New Uncompetitive Inhibitors of Glucose-6-Phosphate Dehydrogenase

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