ArticleMolecular microbiology2010
Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice.
Article in Molecular microbiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
- Design of 2-Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach.Journal of medicinal chemistry · 2025Article
- Comparative metabolism of conjugated and unconjugated pterins in Crithidia, Leishmania and African trypanosomes.PLoS neglected tropical diseases · 2025Article
- In Silico and In Vitro Search for Dual Inhibitors of theMolecules (Basel, Switzerland) · 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
- Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.Journal of medicinal chemistry · 2022Article
- Repurposing the Trypanosomatidic GSK Kinetobox for the Inhibition of Parasitic Pteridine and Dihydrofolate Reductases.Pharmaceuticals (Basel, Switzerland) · 2021Article
- An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases.Molecules (Basel, Switzerland) · 2021Review
- Antileishmanial activity evaluation of thiazolidine-2,4-dione against Leishmania infantum and Leishmania braziliensis.Parasitology research · 2020Article
- An essential thioredoxin-type protein of Trypanosoma brucei acts as redox-regulated mitochondrial chaperone.PLoS pathogens · 2019Article
- Future Prospects in the Treatment of Parasitic Diseases: 2-Amino-1,3,4-Thiadiazoles in Leishmaniasis.Molecules (Basel, Switzerland) · 2019Review
- Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform.SLAS discovery : advancing life sciences R & D · 2019Article
- Identification of Novel Potential Inhibitors of Pteridine Reductase 1 inMolecules (Basel, Switzerland) · 2019Article
- Characterisation of a putative glutamate 5-kinase from Leishmania donovani.The FEBS journal · 2018Article
- Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.PLoS neglected tropical diseases · 2017Article
- Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To InhibitACS omega · 2017Article
- Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.Molecules (Basel, Switzerland) · 2017Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei.The Journal of biological chemistry · 2016Article
- Trypanosoma brucei DHFR-TS Revisited: Characterisation of a Bifunctional and Highly Unstable Recombinant Dihydrofolate Reductase-Thymidylate Synthase.PLoS neglected tropical diseases · 2016Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Gene knockout and knockdown methods were used to examine essentiality of pteridine reductase (PTR1) in pterin metabolism in the African trypanosome. Attempts to generate PTR1 null mutants in bloodstream form Trypanosoma brucei proved unsuccessful; despite integration of drug selectable markers at the target locus, the gene for PTR1 was either retained at the same locus or elsewhere in the genome. However, RNA interference (RNAi) resulted in complete knockdown of endogenous protein after 48 h, followed by cell death after 4 days. This lethal phenotype was reversed by expression of enzymatically active Leishmania major PTR1 in RNAi lines ((oe)RNAi) or by addition of tetrahydrobiopterin to cultures. Loss of PTR1 was associated with gross morphological changes due to a defect in cytokinesis, resulting in cells with multiple nuclei and kinetoplasts, as well as multiple detached flagella. Electron microscopy also revealed increased numbers of glycosomes, while immunofluorescence microscopy showed increased and more diffuse staining for glycosomal matrix enzymes, indicative of mis-localisation to the cytosol. Mis-localisation was confirmed by digitonin fractionation experiments. RNAi cell lines were markedly less virulent than wild-type parasites in mice and virulence was restored in the (oe)RNAi line. Thus, PTR1 may be a drug target for human African trypanosomiasis.
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Registered trials
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