Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense

Suganuma, Keisuke; Sarwono, Albertus Eka Yudistira; Mitsuhashi, Shinya; Jąkalski, Marcin; Okada, Tadashi; Nthatisi, Molefe; Yamagishi, Junya; Ubukata, Makoto; Inoue, Noboru

doi:10.1128/aac.02816-15

Cited by 15 publications

(6 citation statements)

References 23 publications

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“…Mycophenolic acid ( 5 ) is classified as an inosine 5'-monophosphate dehydrogenase inhibitor and the anti-trypanosomal effects of this compound have been identified against T. b. brucei [ 69 ] in addition to many other protozoan parasites [ 70 , 71 ]. We observed activity against T. b. brucei (IC 50 of 0.51 ± 0.10 µM) which correlates with the previously reported IC 50 value [ 72 ]. An IC 50 value of 1.59 ± 0.03 µM was demonstrated in the T. cruzi assay and showed no selectivity, thus effecting the host cell.…”

Section: Discussionsupporting

confidence: 92%

Screening a Natural Product-Based Library against Kinetoplastid Parasites

et al. 2017

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Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (Leishmania donovani DD8, Trypanosoma brucei brucei and Trypanosoma cruzi) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC50 values of the natural products were obtained for L. donovani DD8, T. b. brucei and T. cruzi in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC50 values of ≤10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (1) was the only compound identified with activity across all three investigated parasites, exhibiting IC50 values <5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified.

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Section: Discussionsupporting

confidence: 92%

Screening a Natural Product-Based Library against Kinetoplastid Parasites

et al. 2017

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“…Hence, it is expected that inhibition of IMPDH by MPA deprives the cell of guanine nucleotides. Indeed, exposure of parental BSF cells to MPA resulted in a significant growth inhibition, with similar levels of toxicity to those previously reported 33 (Fig. 3 C).…”

Section: Resultssupporting

confidence: 88%

Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides

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Martínez-Arribas

et al. 2022

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Inosine triphosphate pyrophosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. In this work, we have characterized the Trypanosoma brucei ITPase ortholog (TbITPA). Recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form. Immunolocalization analysis performed in bloodstream forms suggests that the primary role of TbITPA is the exclusion of deaminated purines from the cytosolic nucleoside triphosphate pools. Even though ITPA-knockout bloodstream parasites are viable, they are more sensitive to inhibition of IMP dehydrogenase with mycophenolic acid, likely due to an expansion of IMP, the ITP precursor. On the other hand, TbITPA can also hydrolyze the activated form of the antiviral ribavirin although in this case, the absence of ITPase activity in the cell confers protection against this nucleoside analog. This unexpected phenotype is dependant on purine availability and can be explained by the fact that ribavirin monophosphate, the reaction product generated by TbITPA, is a potent inhibitor of trypanosomal IMP dehydrogenase and GMP reductase. In summary, the present study constitutes the first report on a protozoan inosine triphosphate pyrophosphatase involved in the removal of harmful deaminated nucleotides from the cytosolic pool.

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“…The specimens were blocked with 5 % skim milk in TBS supplemented with 0.05 % tween for 1 h at room temperature. The specimens were then incubated with a primary antibody (anti-recombinant T. congolense α-tubulin serum) [ 19 ]. Next, the slides were incubated with a secondary antibody (Alexa Fluor 488 goat anti-rabbit IgG [H + L], Thermo Fisher Scientific K.K.)…”

Section: Methodsmentioning

confidence: 99%

Isolation, cultivation and molecular characterization of a new Trypanosoma equiperdum strain in Mongolia

et al. 2016

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BackgroundTrypanosoma equiperdum causes dourine via sexual transmission in Equidae. T. equiperdum is classified under the subgenus Trypanozoon along with the T. brucei sspp. and T. evansi; however, the species classification of Trypanozoon remains a controversial topic due to the limited number of T. equiperdum reference strains. In addition, it is possible that some were misclassified T. evansi strains. Thus, there is a strong need for a new T. equiperdum strain directly isolated from the genital mucosa of a horse with a clinically- and parasitologically-confirmed dourine infection.MethodsTrypanosomes isolated from the urethral tract of a stallion with suspected dourine, were directly cultivated using soft agarose media at 37 °C in 5 % CO2. For molecular characterization, 18S ribosomal RNA (rRNA) gene, the internal transcribed spacer (ITS) and 8 maxicircle DNA regions were amplified by a PCR and their sequences were determined. To analyze the ratio of the kinetoplastic/akinetoplastic population, the kinetoplasts and the nuclei of trypanosomes were subjected to Hoechst staining and observed by fluorescence microscopy.ResultsIn addition to the clinical symptoms and the molecular diagnosis, this stallion was definitively diagnosed with dourine by the detection of trypanosomes in the urethral mucosa. These results strongly suggested that the isolated trypanosome was true T. equiperdum. T. equiperdum isolated from the urethral tract was adapted in vitro using soft agarose media. Based on the results of a phylogenetic analysis of 18S rRNA and ITS, this T. equiperdum isolate was classified into the Trypanozoon clade. In a PCR of the maxicircle DNA region, only NADH-dehydrogenase subunits 4 and 5 was amplified. Clear kinetoplasts were observed in most of the T. equiperdum isolates. In contrast, most culture-adapted T. equiperdum were of the akinetoplastic form.ConclusionWe concluded that our isolated trypanosome was the first confirmed case of T. equiperdum in Mongolia and named it “T. equiperdum IVM-t1”. T. equiperdum IVM-t1 was well adapted and propagated in soft agarose media, which indicates that this culture method is useful for isolation of T. equiperdum from horses with dourine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-016-1755-3) contains supplementary material, which is available to authorized users.

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Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense

Cited by 15 publications

References 23 publications

Screening a Natural Product-Based Library against Kinetoplastid Parasites

Screening a Natural Product-Based Library against Kinetoplastid Parasites

Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides

Isolation, cultivation and molecular characterization of a new Trypanosoma equiperdum strain in Mongolia

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