Evaluation of the effect of guanabenz-loaded nanoparticles on chronic toxoplasmosis in mice

Elgendy, Wesam Moustafa Abdelhamid; Haggag, Yusuf A.; El-Nouby, Kholoud A; El-Kowrany, Samy Ibrahim; Marhoumy, Sirria Mostafa El

doi:10.1016/j.exppara.2023.108460

Cited by 2 publications

(2 citation statements)

References 26 publications

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“…Additionally, the distinctive cyst wall is highly resistant to most of anti-T. gondii drugs and consequently no clinical treatment is available for tissue cyst. 49 Based on guanabenz-loaded nanoparticles for enhancing drug delivery and an amenable dual luciferase system for determining bradyzoite viability, 50,51 the use of modified inhibitors targeting TgDHO and other catalytic enzymes of bradyzoites may further improve the therapeutic effect of chronic toxoplasmosis.…”

Section: Discussionmentioning

confidence: 99%

Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti‐parasitic target

Pan,

Ge,

Niu

et al. 2023

The FASEB Journal

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Toxoplasma gondii relies heavily on the de novo pyrimidine biosynthesis pathway for fueling the high uridine‐5′‐monophosphate (UMP) demand during parasite growth. The third step of de novo pyrimidine biosynthesis is catalyzed by dihydroorotase (DHO), a metalloenzyme that catalyzes the reversible condensation of carbamoyl aspartate to dihydroorotate. Here, functional analyses of TgDHO reveal that tachyzoites lacking DHO are impaired in overall growth due to decreased levels of UMP, and the noticeably growth restriction could be partially rescued after supplementation with uracil or high concentrations of L‐dihydroorotate in vitro. When pyrimidine salvage pathway is disrupted, both DHOH35A and DHOD284E mutant strains proliferated much slower than DHO‐expressing parasites, suggesting an essential role of both TgDHO His35 and Asp284 residues in parasite growth. Additionally, DHO deletion causes the limitation of bradyzoite growth under the condition of uracil supplementation or uracil deprivation. During the infection in mice, the DHO‐deficient parasites are avirulent, despite the generation of smaller tissue cysts. The results reveal that TgDHO contributes to parasite growth both in vitro and in vivo. The significantly differences between TgDHO and mammalian DHO reflect that DHO can be exploited to produce specific inhibitors targeting apicomplexan parasites. Moreover, potential DHO inhibitors exert beneficial effects on enzymatic activity of TgDHO and T. gondii growth in vitro. In conclusion, these data highlight the important role of TgDHO in parasite growth and reveal that it is a promising anti‐parasitic target for future control of toxoplasmosis.

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Section: Discussionmentioning

confidence: 99%

Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti‐parasitic target

Pan,

Ge,

Niu

et al. 2023

The FASEB Journal

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“…When mature bradyzoites were treated with the compounds, Bay 11-7085 resulted in an increase in bradyzoite numbers (Figure 5 d), appearing to induce a stress response that supersedes its ability to block nuclear transport. Importantly, small molecules must penetrate the cyst wall of bradyzoites, and novel methods for delivery of Bay 11-7085 may need to be developed 52 . Further validation of TgIMP as the target of Bay 11-7085 in vivo will confirm these preliminary findings.…”

Section: Gw5074 and Cape Inhibit Nuclear Localisation In P Falciparum...mentioning

confidence: 99%

Importin α inhibitors act against the differentiated stages of apicomplexan parasitesPlasmodium falciparumandToxoplasma gondii

Bhambid,

Walunj,

C. A.

et al. 2024

Preprint

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Protozoan parasites of the phylum Apicomplexa, includingPlasmodium falciparumandToxoplasma gondii, cause widespread disease in humans. New drugs and protein targets are required for the treatment of these diseases, particularly therapies targeting multiple stages of the parasite life cycles. Nuclear import, carried out by the transporter’s importin (IMP) α and β subunits, is a valid target for the discovery of lead compounds against these protozoan parasites: small molecules were identified that inhibit interactions between IMPα and nuclear localisation signalsin vitroand also inhibit the growth of the rapidly-dividing stages ofP. falciparumandT. gondii(asexual stages and tachyzoites) in culture. In this report, we add another small molecule (Bay 11-7082) to the panel of inhibitors of IMPα and test the ability of these inhibitors to first, inhibit nuclear transport in the rapidly dividing stages and, next, the maturation of differentiated stages of both parasites. We show that GW5074 and CAPE inhibit nuclear transport in theP. falciparumblood stages, while Bay 11-7085 inhibits nuclear transport inT. gondiitachyzoites. Interestingly, CAPE strongly inhibits gametocyte maturation, the sexual stages ofP. falciparum, and Bay 11-7085 weakly inhibits bradyzoite differentiation, the latent stages ofT. gondii. As differentiation of both these stages is dependent on activation of gene expression, triggered by the nuclear translocation of transcription factors, our work provides a “proof of concept” that targeting nuclear import is a viable strategy for the development of therapeutics against multiple stages of apicomplexan parasites, some of them recalcitrant to existing drugs.

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Evaluation of the effect of guanabenz-loaded nanoparticles on chronic toxoplasmosis in mice

Cited by 2 publications

References 26 publications

Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti‐parasitic target

Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti‐parasitic target

Importin α inhibitors act against the differentiated stages of apicomplexan parasitesPlasmodium falciparumandToxoplasma gondii

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