ArticleProceedings of the National Academy of Sciences of the United States of America1998
Down-regulation of Leishmania donovani trypanothione reductase by heterologous expression of a trans-dominant mutant homologue: effect on parasite intracellular survival.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
42 citing papers in PubMed, 169 citations in OpenAlex.
- Quantitative proteomics of infected macrophages reveals novel Leishmania virulence factors.PLoS pathogens · 2026Article
- Review
- Fragment Merging, Growing, and Linking Identify New Trypanothione Reductase Inhibitors for Leishmaniasis.Journal of medicinal chemistry · 2024Article
- Anti-leishmanial activity ofFrontiers in chemistry · 2024Article
- Assessing proteases and enzymes of the trypanothione system in subpopulations of Leishmania (Viannia) braziliensis Thor strain during macrophage infection.Memorias do Instituto Oswaldo Cruz · 2024Article
- In Silico Exploration of the Trypanothione Reductase (TryR) ofInternational journal of molecular sciences · 2023Article
- Tackling Sleeping Sickness: Current and Promising Therapeutics and Treatment Strategies.International journal of molecular sciences · 2023Review
- Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Screening of medicinal plants unraveled the leishmanicidal credibility ofJournal of parasitic diseases : official organ of the Indian Society for Parasitology · 2022Article
- Oral Efficacy of a Diselenide Compound Loaded in Nanostructured Lipid Carriers in a Murine Model of Visceral Leishmaniasis.ACS infectious diseases · 2021Article
- Druggable hot spots in trypanothione reductase: novel insights and opportunities for drug discovery revealed by DRUGpy.Journal of computer-aided molecular design · 2021Article
- Antileishmanial activity evaluation of a natural amide and its synthetic analogs against Leishmania (V.) braziliensis: an integrated approach in vitro and in silico.Parasitology research · 2021Article
- Identification of 3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors against Trypanothione Reductase fromMolecules (Basel, Switzerland) · 2021Article
- Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases.Molecules (Basel, Switzerland) · 2020Review
- Protective or Detrimental? Understanding the Role of Host Immunity in Leishmaniasis.Microorganisms · 2019Review
- Complete assembly of the Leishmania donovani (HU3 strain) genome and transcriptome annotation.Scientific reports · 2019Article
- Understanding the Cross-Talk of Redox Metabolism and Fe-S Cluster Biogenesis in Leishmania Through Systems Biology Approach.Frontiers in cellular and infection microbiology · 2019Article
- Genetic Manipulation of Leishmania donovani to Explore the Involvement of Argininosuccinate Synthase in Oxidative Stress Management.PLoS neglected tropical diseases · 2016Article
- Molecular mechanisms of in vitro betulin-induced apoptosis of Leishmania donovani.The American journal of tropical medicine and hygiene · 2014Article
- Genetically modified organisms and visceral leishmaniasis.Frontiers in immunology · 2014Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
A trans-dominant mutational strategy was used to down-regulate trypanothione reductase (TR) activity levels in Leishmania donovani, the causative agent of visceral leishmaniasis in humans. TR, regarded as an ideal drug target against trypanosomatid infections, is a homodimeric flavoprotein oxidoreductase unique to these organisms that plays a central role in the enzymatic regeneration of the thiol pool. Extrachromosomal, heterologous expression of a trans-dominant mutant version of the Trypanosoma cruzi enzyme in L. donovani resulted in the formation of inactive cross-species heterodimers and in a dramatic decrease of endogenous TR activity levels. Recombinant cells depleted of up to 85% of TR activity were significantly impaired in their ability to regenerate dihydrotrypanothione from trypanothione disulfide following oxidation with diamide. Nonetheless trans-dominant mutant recombinants were still capable of maintaining a reduced intracellular environment during cell growth in culture and were able to metabolize hydrogen peroxide at wild-type rates in vitro. Importantly, however, cells expressing the trans-dominant mutant enzyme displayed a decreased ability to survive inside activated macrophages in a murine model of Leishmania infection. The apparent inability of Leishmania to modulate the expression of active TR homodimers in response to the expression of trans-dominant mutant protein suggests that specific inhibitors of this enzyme should be useful anti-leishmanial agents.
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Registered trials
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