Tranylcypromine

Frieling, Helge; Bleich, Stefan

doi:10.1007/s00406-006-0660-8

Cited by 45 publications

(19 citation statements)

References 56 publications

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“…MC3935 was synthesized based on the scaffold of the nonselective and irreversible monoamine oxidase (MAO) inhibitor tranylcypromine (TCP) [29,42]. Tranylcypromine is a mechanism-based suicide inhibitor of MAO and LSD1; it covalently binds to the FAD cofactor embedded within the protein, thus abolishing enzymatic catalysis [43].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Carneiro

Silva

Amaral

et al. 2019

Preprint

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Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ), and due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935. We synthesized a novel and potent LSD1 inhibitor, MC3935, which was used to treat schistosomula or adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.Author SummarySchistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminth Schistosoma mansoni. The control and treatment of the disease rely almost exclusively on praziquantel (PZQ). Thus, there is an urgent need to search for promising protein targets to develop new drugs. Drugs that inhibit enzymes that modify the chromatin structure have been developed for a number of diseases. We and others have shown that S. mansoni epigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of the S. mansoni histone demethylase LSD1 (SmLSD1) as a drug target. We reported the synthesis of a novel and potent LSD1 inhibitor, MC3935, and show that it selectively inhibited the enzymatic activity of SmLSD1. Treatment of juvenile or adult worms with MC3935 caused severe damage to the tegument of the parasites and compromised egg production. Importantly, MC3935 proved to be highly toxic to S. mansoni, culminating in the death of juvenile or adult worms within 96 h. Transcriptomic analysis of MC3935-treated parasites revealed changes in the gene expression of hundreds of genes involved in key biological processes. Importantly, SmLSD1 contains unique sequences within its polypeptide chain that could be explored to develop a S. mansoni selective drug.

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Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Carneiro

Silva

Amaral

et al. 2019

Preprint

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“…This study demonstrates that LSD1 plays a crucial role in fetal γ-globin silencing and that an LSD1 inhibitor, TCP, can enhance HbF synthesis. TCP has been widely used as an antidepressant with manageable side effects; it exerts its antidepressive effect by elevating serotonin levels 18 and does not seem to have cytotoxic or mutagenic effects. Although it was recently reported that LSD1 inhibition by RNAi in mice can cause hematopoietic defects 19 , hematological toxicity has not been associated with TCP in humans except in rare cases of transient thrombocytopenia attributable to overdosing 20 .…”

mentioning

confidence: 99%

Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction

Shi

Cui

Engel

et al. 2013

Nat Med

151

145

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Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin–inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin–transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.

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“…The new findings in the present study are: 1) endogenous PGI 2 production mediates nonneuronal COX-2-dependent neuroprotection; 2) PGI 2 is produced by a subset of infiltrating neutrophils that populate the lesion core in response to excitotoxin administration; and 3) PGI 2 can exert neuroprotective effects by directly reducing NMDA-mediated excess calcium influx. There is a significant clinical implication resulting from the observation that endogenous PGI 2 has a neuroprotective effect: the PGIS inhibitor tranylcypromine is also an inhibitor of monoamine oxidase, and this drug is used clinically as an antidepressant;20 consequently, patients on tranylcypromine therapy may have an increased risk of exacerbated neural damage in response to acute brain injury.…”

Section: Discussionmentioning

confidence: 99%

Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury

Belevych

Wang

et al. 2014

JIR

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In a previous study, we found that intracerebral administration of excitotoxin (RS)-(tetrazole-5yl) glycine caused increased neural damage in the brain in an endothelial COX-2 deleted mouse line (Tie2Cre COX-2flox/flox). In this study, we investigated whether prostacyclin might mediate this endothelial COX-2-dependent neuroprotection. Administration of excitotoxin into the striatum induced the production of prostacyclin (PGI2) in wild type, but not in endothelial COX-2 deleted mice. Inhibition of PGI2 synthase exacerbated brain lesions induced by the excitotoxin in wild type, but not in endothelial COX-2 deleted mice. Administration of a PGI2 agonist reduced neural damage in both wild type and endothelial COX-2 deleted mice. Increased PGI2 synthase expression was found in infiltrating neutrophils. In an ex vivo assay, PGI2 reduced the excitotoxin-induced calcium influx into neurons, suggesting a cellular mechanism for PGI2 mediated neuroprotection. These results reveal that PGI2 mediates endothelial COX-2 dependent neuroprotection.

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Tranylcypromine

Cited by 45 publications

References 56 publications

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Lysine-specific demethylase 1 is a therapeutic target for fetal hemoglobin induction

Prostacyclin mediates endothelial COX-2-dependent neuroprotective effects during excitotoxic brain injury

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