ArticlePLoS neglected tropical diseases2018
Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery.
Article in PLoS neglected tropical diseases, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 50 citations in OpenAlex.
- Reversal of ATP synthase is a key attribute accompanying cellular differentiation of Trypanosoma brucei insect forms.Communications biology · 2026Article
- Development of Prolinol Containing Inhibitors of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase: Rational Structure-Based Drug Design.Journal of medicinal chemistry · 2024Article
- Kinetic and Structural Characterization ofBiochemistry · 2023Article
- Targeting Metalloenzymes: The "Achilles' Heel" of Viruses and Parasites.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Kinetic Characterization and Inhibition ofBiochemistry · 2022Article
- Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides.Scientific reports · 2022Article
- Characterization of adenine phosphoribosyltransferase (APRT) activity in Trypanosoma brucei brucei: Only one of the two isoforms is kinetically active.PLoS neglected tropical diseases · 2022Article
- Phosphonates and Phosphonate Prodrugs in Medicinal Chemistry: Past Successes and Future Prospects.Frontiers in chemistry · 2022Review
- Divergent metabolism between Trypanosoma congolense and Trypanosoma brucei results in differential sensitivity to metabolic inhibition.PLoS pathogens · 2021Article
- Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro.Scientific reports · 2021Article
- Article
- Nucleoside Hydrolase NH 36: A Vital Enzyme for theFrontiers in immunology · 2019Review
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites' viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 μM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.
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