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Review
. 2023 Apr-May;27(4-5):293-304.
doi: 10.1080/14728222.2023.2217353. Epub 2023 May 24.

Toxoplasma gondii infection: novel emerging therapeutic targets

Affiliations
Review

Toxoplasma gondii infection: novel emerging therapeutic targets

Joachim Müller et al. Expert Opin Ther Targets. 2023 Apr-May.

Abstract

Introduction: Toxoplasmosis constitutes a challenge for public health, animal production, and welfare. So far, only a limited panel of drugs has been marketed for clinical applications. In addition to classical screening, the investigation of unique targets of the parasite may lead to the identification of novel drugs.

Areas covered: Herein, the authors describe the methodology to identify novel drug targets in Toxoplasma gondii and review the literature with a focus on the last two decades.

Expert opinion: Over the last two decades, the investigation of essential proteins of T. gondii as potential drug targets has fostered the hope of identifying novel compounds for the treatment of toxoplasmosis. Despite good efficacies in vitro, only a few classes of these compounds are effective in suitable rodent models, and none has cleared the hurdle to applications in humans. This shows that target-based drug discovery is in no way better than classical screening approaches. In both cases, off-target effects and adverse side effects in the hosts must be considered. Proteomics-driven analyses of parasite- and host-derived proteins that physically bind drug candidates may constitute a suitable tool to characterize drug targets, irrespectively of the drug discovery methods.

Keywords: Apicomplexa; drug development; drug targets; host–parasite interactions; proteomics.

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Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
The workflows of target and screening based drug development strategies. Both strategies are interlinked.
Figure 2.
Figure 2.
The strategy to use affinity chromatography to identify drug binding proteins is a direct consequence of the drug-target paradigm. LC, liquid chromatography; MS, mass spectrometry; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis.
Figure 3.
Figure 3.
Structural hallmarks of T. gondii tachyzoites visualized by TEM. A and B show T. gondii tachyzoites were cultured in human foreskin fibroblast monolayers during 36 h (A, B) and 72 h. The boxed area in A is shown at higher magnification in B. Tachyzoites reside and proliferate in the host cell cytoplasm inside a parasitophorous vacuole, surrounded by a parasitophorous vacuole membrane (small arrows). In rapidly proliferating cultures, tachyzoites are often seen still attached to the residual body (rb) (B). Parasites exhibit a single nucleus and an apically located conoid (con), which in conjunction with secretory organelles such as micronemes (mic), rhoptries (rop) and dense granules (dg) forms the apical complex. Tachyzoites harbor a single mitochondrion (mito) of which, depending on the section plane, only parts are visible. The mitochondrion contains an electron dense matrix and clearly discernible cristae. After 72 h (C), large vacuoles containing numerous newly formed tachyzoites are visible, which will eventually undergo egress and infect neighboring host cells. Bars in A = 2.2 μm, B = 0.35 μm, C = 1.5 μm. TEM was performed as described elsewhere [134].
Figure 4.
Figure 4.
Structural alterations induced by in vitro drug treatments of T. gondii tachyzoites. Tachyzoites were grown in HFF and treated with either dicationic pentamidine derivatives such as DB745 (A, B), the bumped kinase inhibitor BKI-1748 (C, D), and mitochondrial inhibitors such as Decoquinate (E) or the endochin-like quinolone ELQ-334. Within 24 h of treatment (A), pentamidine derivatives induce the formation of cytoplasmic lipid droplets (ld) and vacuoles (vac) that contain electron dense material of unknown nature resembling autophagosomes, while the mitochondrion still appears unaffected. After 72 h (B), most tachyzoites become structurally heavily impaired demonstrating parasiticidal activity of DB745. C shows a multinucleated complex (MNC) generated after upon treatment of T. gondii tachyzoites with BKI-1748, in D the boxed area is shown at higher magnification. The MNC is located within a parasitophorous vacuole, the membrane of which is indicated with horizontal arrows and the MNC is embedded in. a granular and electron dense matrix (C). Note the presence of multiple nuclei. At higher magnification (D), the small apical complexes that eventually form the anterior part of newly formed zoites are indicated by diagonal arrows. Newly formed zoites lack the characteristic triple plasma membrane of T. gondii tachyzoites, are deficient in completing cytokinesis, and remain stuck within the host cell. The mitochondrion (mito) within these MNCs appears unaffected. In contrast, compounds such as DCQ (E)and ELQ-334(F) induce the rapid loss of the electron dense mitochondrial matrix and cristae within 6–12 h of treatment, and induce mictochondrial swelling, while other organelles such as rhoptries (rop), micronemes (mic), dense granules (dg), and the Golgi apparatus remain structurally unaffected, demonstrating that the mitochondrion is the primary target. Bars in A = 0.88 μm, B = 0.35 μm, C = 1.2 μm, D = 0.4 μm, E and F = 0.46 μm. TEM was performed as described elsewhere [92].

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