Inhibition and Structure of Toxoplasma gondii Purine Nucleoside Phosphorylase

Donaldson, Teraya; Cassera, María B.; Ho, M.; Zhan, Changhong; Merino, Emilio F.; Evans, Gary B.; Tyler, Peter C.; Almo, Steven C.; Schramm, Vern L.; Kim, Kami

doi:10.1128/ec.00308-13

Cited by 20 publications

(17 citation statements)

References 41 publications

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“…There are four homologous genes encoding nucleoside transporters in C. cayetanensis (Table 3 ). In addition, the presence of an adenosine kinase (AdK) indicates that adenosine may be the major purine utilized by C. cayetanensis , in contrast to the AMP used by P. falciparum [ 17 , 18 ]. Like most other apicomplexans except Cryptosporidium spp., C. cayetanensis possesses all the enzymes for synthesizing pyrimidine de novo from aspartate and glutamine, except for the orotate phosphoribosyl transferase that catalyzes the phosphorylation of orotate using PRPP.…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics reveals Cyclospora cayetanensis possesses coccidia-like metabolism and invasion components but unique surface antigens

et al. 2016

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BackgroundCyclospora cayetanensis is an apicomplexan that causes diarrhea in humans. The investigation of foodborne outbreaks of cyclosporiasis has been hampered by a lack of genetic data and poor understanding of pathogen biology. In this study we sequenced the genome of C. cayetanensis and inferred its metabolism and invasion components based on comparative genomic analysis.ResultsThe genome organization, metabolic capabilities and potential invasion mechanism of C. cayetanensis are very similar to those of Eimeria tenella. Propanoyl-CoA degradation, GPI anchor biosynthesis, and N-glycosylation are some apparent metabolic differences between C. cayetanensis and E. tenella. Unlike Eimeria spp., there are no active LTR-retrotransposons identified in C. cayetanensis. The similar repertoire of host cell invasion-related proteins possessed by all coccidia suggests that C. cayetanensis has an invasion process similar to the one in T. gondii and E. tenella. However, the significant reduction in the number of identifiable rhoptry protein kinases, phosphatases and serine protease inhibitors indicates that monoxenous coccidia, especially C. cayetanensis, have limited capabilities or use a different system to regulate host cell nuclear activities. C. cayetanensis does not possess any cluster of genes encoding the TA4-type SAG surface antigens seen in E. tenella, and may use a different family of surface antigens in initial host cell interactions.ConclusionsOur findings indicate that C. cayetanensis possesses coccidia-like metabolism and invasion components but unique surface antigens. Amino acid metabolism and post-translation modifications of proteins are some major differences between C. cayetanensis and other apicomplexans. The whole genome sequence data of C. cayetanensis improve our understanding of the biology and evolution of this major foodborne pathogen and facilitate the development of intervention measures and advanced diagnostic tools.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2632-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Comparative genomics reveals Cyclospora cayetanensis possesses coccidia-like metabolism and invasion components but unique surface antigens

et al. 2016

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“…Another immucillin, IH inhibits the PNP of Toxoplasma gondii [ 39 ], the NH of Leishmania (L . ) donovani [ 29 ] and human PNP [ 40 – 42 ].…”

Section: Discussionmentioning

confidence: 99%

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

et al. 2015

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BackgroundImmucillins ImmA (IA), ImmH (IH) and SerMe-ImmH (SMIH) are synthetic deazapurine nucleoside analogues that inhibit Leishmania (L.) infantum chagasi and Leishmania (L.) amazonensis multiplication in vitro without macrophage toxicity. Immucillins are compared to the Glucantime standard drug in the chemotherapy of Leishmania (L.) infantum chagasi infection in mice and hamsters. These agents are tested for toxicity and immune system response.Methodology/Principal FindingsBALB/c mice were infected with 107 amastigotes, treated with IA, IH, SMIH or Glucantime (2.5mg/kg/day) and monitored for clinical variables, parasite load, antibody levels and splenocyte IFN-γ, TNF-α, and IL-10 expression. Cytokines and CD4+, CD8+ and CD19+ lymphocyte frequencies were assessed in uninfected controls and in response to immucillins. Urea, creatinine, GOT and GPT levels were monitored in sera. Anti-Leishmania-specific IgG1 antibodies (anti-NH36) increased in untreated animals. IgG2a response, high levels of IFN-γ, TNF-α and lower levels of IL-10 were detected in mice treated with the immucillins and Glucantime. Immucillins permitted normal weight gain, prevented hepato-splenomegaly and cleared the parasite infection (85–89%) without renal and hepatic toxicity. Immucillins promoted 35% lower secretion of IFN-γ in uninfected controls than in infected mice. IA and IH increased the CD4+ T and CD19+ B cell frequencies. SMIH increased only the proportion of CD-19 B cells. IA and IH also cured infected hamsters with lower toxicity than Glucantime.Conclusions/SignificanceImmucillins IA, IH and SMIH were effective in treating leishmaniasis in mice. In hamsters, IA and IH were also effective. The highest therapeutic efficacy was obtained with IA, possibly due to its induction of a TH1 immune response. Low immucillin doses were required and showed no toxicity. Our results disclose the potential use of IA and IH in the therapy of visceral leishmaniasis.

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“…The docking result was treated with DS Client. In this study, three crystal structures of the proteins were selected for docking, PDB ID: 6BFA (calcium-dependent protein kinase 1) 21 , 1LII (adenosine kinase) 22 and 3MB8 (purine nucleoside phosphorylase) 23 . The different xyz coordinates and radii of these proteins were defined as the binding site spheres.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

Luan

Jin

Gong

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Ursolic acid ( UA ), a plant-derived compound, has many properties beneficial to health. In the present study, we synthesised three series of novel UA derivatives and evaluated their anti- Toxoplasma gondii activity both in vitro and in vivo . Most derivatives exhibited an improved anti- T. gondii activity in vitro when compared with UA (parent compound), whereas compound 3d exhibited the most potent anti- T. gondii activity in vivo . Spiramycin served as the positive control. Additionally, determination of biochemical parameters, including the liver and spleen indexes, indicated compound 3d to effectively reduce hepatotoxicity and significantly enhance anti-oxidative effects, as compared with UA . Furthermore, our molecular docking study indicated compound 3d to possess a strong binding affinity for T. gondii calcium-dependent protein kinase 1 (TgCDPK1). Based on these findings, we conclude that compound 3d , a derivative of UA , could act as a potential inhibitor of TgCDPK1.

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Inhibition and Structure of Toxoplasma gondii Purine Nucleoside Phosphorylase

Cited by 20 publications

References 41 publications

Comparative genomics reveals Cyclospora cayetanensis possesses coccidia-like metabolism and invasion components but unique surface antigens

Comparative genomics reveals Cyclospora cayetanensis possesses coccidia-like metabolism and invasion components but unique surface antigens

Immucillins ImmA and ImmH Are Effective and Non-toxic in the Treatment of Experimental Visceral Leishmaniasis

Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

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