ArticleAntimicrobial agents and chemotherapy2010
Evaluation of nucleoside hydrolase inhibitors for treatment of African trypanosomiasis.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Discovery of Trypanosoma brucei inhibitors enabled by a unified synthesis of diverse sulfonyl fluorides.Communications chemistry · 2024Article
- Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.International journal for parasitology. Drugs and drug resistance · 2024Review
- Ribonucleoside Hydrolases-Structure, Functions, Physiological Role and Practical Uses.Biomolecules · 2023Review
- Structure, Oligomerization and Activity Modulation in N-Ribohydrolases.International journal of molecular sciences · 2022Review
- Acyclic nucleoside phosphonates with adenine nucleobase inhibit Trypanosoma brucei adenine phosphoribosyltransferase in vitro.Scientific reports · 2021Article
- Reverse C-glycosidase reaction provides C-nucleotide building blocks of xenobiotic nucleic acids.Nature communications · 2020Article
- Article
- Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness.Nature communications · 2019Article
- Structural explanation for the tunable substrate specificity of an E. coli nucleoside hydrolase: insights from molecular dynamics simulations.Journal of computer-aided molecular design · 2018Article
- Druggability of the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis.Chemical biology & drug design · 2018Article
- Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy.International journal for parasitology. Drugs and drug resistance · 2017Article
- Structural and biochemical characterization of the nucleoside hydrolase from C. elegans reveals the role of two active site cysteine residues in catalysis.Protein science : a publication of the Protein Society · 2017Article
- Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase.Scientific reports · 2016Article
- Trypanosoma brucei Methylthioadenosine Phosphorylase Protects the Parasite from the Antitrypanosomal Effect of Deoxyadenosine: IMPLICATIONS FOR THE PHARMACOLOGY OF ADENOSINE ANTIMETABOLITES.The Journal of biological chemistry · 2016Article
- In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors.Advances in bioinformatics · 2015Article
- Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines.Molecular pharmacology · 2013Article
- Pyrimidine biosynthesis is not an essential function for Trypanosoma brucei bloodstream forms.PloS one · 2013Article
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16 authors.
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Abstract
In this paper, we present the biochemical and biological evaluation of N-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of Trypanosoma vivax inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were tested against bloodstream-form Trypanosoma brucei brucei, only one inhibitor, N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (UAMC-00363), displayed significant activity (mean 50% inhibitory concentration [IC(50)] +/- standard error, 0.49 +/- 0.31 microM). Validation in an in vivo model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against T. b. brucei IAG-NH and inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on T. vivax IAG-NH. Second, to verify the uptake of these compounds by T. b. brucei, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of T. b. brucei were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of T. b. brucei displayed no resistance to the compound. Consequently, no cross-resistance to the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic T. b. brucei (IAG-NH, IG-NH, and methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from all these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of T. b. brucei and that, therefore, it is possible that UAMC-00363 acts on an additional target.
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