Treatment of toxoplasmosis: Current options and future perspectives

Konstantinović, Neda; Guegan, Hélène; Štajner, Tijana; Belaz, Sorya; Robert‐Gangneux, Florence

doi:10.1016/j.fawpar.2019.e00036

Cited by 136 publications

(121 citation statements)

References 139 publications

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“…Under specific circumstances, bradyzoites can reconvert to actively replicating tachyzoites, which induces inflammation and contributes to disease progression (3). While therapeutics exist to effectively combat tachyzoites, there is currently no fully effective treatment for bradyzoites (4). A better understanding of how bradyzoites persist is necessary to inform rationale therapeutic targeting of this elusive stage of T. gondii.…”

Section: Introductionmentioning

confidence: 99%

Acquisition of Host Cytosolic Protein by Toxoplasma gondii Bradyzoites

Kannan

Thaprawat

Schultz

et al. 2020

Preprint

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Toxoplasma gondii is a protozoan parasite that persists in the central nervous system as intracellular chronic stage bradyzoites that are encapsulated by a thick cyst wall. While the cyst wall separates bradyzoites from the host cytosol, it has been posited that small solutes can traverse the cyst wall to sustain bradyzoites. Recently it was found that host cytosolic macromolecules can cross the parasitophorous vacuole and are ingested and digested by actively replicating acute stage tachyzoites. However, the extent to which bradyzoites have an active ingestion pathway remained unknown. To interrogate this, we modified previously published protocols that look at tachyzoite acquisition and digestion of host proteins by measuring parasite accumulation of a host-expressed reporter protein after impairment of an endolysosomal protease (Cathepsin Protease L, CPL). Using two cystogenic parasite strains (ME49 and Pru), we demonstrate that T. gondii bradyzoites can ingest host-derived cytosolic mCherry. Bradyzoites acquire host mCherry within 4 hours of invasion and post-cyst wall formation. This study provides direct evidence that host macromolecules can be internalized by T. gondii bradyzoites across the cyst wall in infected cells.

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Section: Introductionmentioning

confidence: 99%

Acquisition of Host Cytosolic Protein by Toxoplasma gondii Bradyzoites

Kannan

Thaprawat

Schultz

et al. 2020

Preprint

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“…Atovaquone, which is commonly applied for the treatment of toxoplasmosis, was used as positive control and displayed the highest activity and selectivity. [9] However, the toxicity of the most bisnaphthoquinones (except for 1a and 1h) to Vero cells was distinctly lower when compared with atovaquone. In contrast to this varied spectrum of activities against T. gondii, all compounds, except 1a and 1i which displayed low double-digit IC 50 values, were virtually inactive against T. b. brucei cells.…”

Section: Resultsmentioning

confidence: 92%

“…Like 1a , the pentafluorophenyl derivative 1h was more toxic to normal Vero cells than to T. gondii cells. Atovaquone, which is commonly applied for the treatment of toxoplasmosis, was used as positive control and displayed the highest activity and selectivity . However, the toxicity of the most bis‐naphthoquinones (except for 1a and 1h ) to Vero cells was distinctly lower when compared with atovaquone.…”

Section: Resultsmentioning

confidence: 99%

New Antiparasitic Bis‐Naphthoquinone Derivatives

Jentzsch

Koko

Nasr

et al. 2020

Chemistry & Biodiversity

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A series of bis‐naphthoquinone derivatives prepared by condensation of aryl aldehydes with lawsone were tested for antiparasitic activities against Toxoplasma gondii and Trypanosoma brucei parasites. Monofluorophenyl derivative 1a, 3,4‐difluorophenyl analog 1c and furyl compound 1l exhibited significant activity against T. gondii cells and appear to be new promising drug candidates against this parasite. The 3,4,5‐trifluorophenyl derivative 1g and the isovanillyl derivative 1j displayed selective activity against Leishmania major amastigotes.

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“…Therapies and candidates for toxoplasmosis have been reviewed elsewhere [19,[31][32][33][34] and, therefore, for the scope of this work, our aim is to discuss and further explore those classes of compounds that are active and/or promising against infections by T. gondii, with a previous or current impact on malaria.…”

Section: Can Antimalarials Treat Toxoplasmosis?mentioning

confidence: 99%

“…The apicomplexan cytochrome bc1 complex is highly conserved within the phylum, including The apicomplexan cytochrome bc1 complex is highly conserved within the phylum, including in T. gondii, with the latter being significantly affected by endochin-like quinolones at both the Qo and Qi sites of this enzyme complex [33,[40][41][42]. In fact, ELQs revealed high efficacies, with single-dose cures being observed in some cases, and, as such, some ELQs entered the preclinical phase of development both against toxoplasmosis and malaria [40,51,52].…”

Section: Endochin-like Oxoquinolines (Elqs) and Quinoline-based Ppq-8mentioning

confidence: 99%

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

et al. 2020

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Toxoplasmosis is an infectious disease with paramount impact worldwide, affecting many vulnerable populations and representing a significant matter of concern. Current therapies used against toxoplasmosis are based essentially on old chemotypes, which fail in providing a definitive cure for the disease, placing the most sensitive populations at risk for irreversible damage in vital organs, culminating in death in the most serious cases. Antimalarial drugs have been shown to possess key features for drug repurposing, finding application in the treatment of other parasite-borne illnesses, including toxoplasmosis. Antimalarials provide the most effective therapeutic solutions against toxoplasmosis and make up for the majority of currently available antitoxoplasmic drugs. Additionally, other antiplasmodial drugs have been scrutinized and many promising candidates have emanated in recent developments. Available data demonstrate that it is worthwhile to explore the activity of classical and most recent antimalarial chemotypes, such as quinolines, endoperoxides, pyrazolo[1,5-a]pyrimidines, and nature-derived peptide-based parasiticidal agents, in the context of toxoplasmosis chemotherapy, in the quest for encountering more effective and safer tools for toxoplasmosis control or eradication.

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Treatment of toxoplasmosis: Current options and future perspectives

Cited by 136 publications

References 139 publications

Acquisition of Host Cytosolic Protein by Toxoplasma gondii Bradyzoites

Acquisition of Host Cytosolic Protein by Toxoplasma gondii Bradyzoites

New Antiparasitic Bis‐Naphthoquinone Derivatives

Antimalarial Agents as Therapeutic Tools Against Toxoplasmosis—A Short Bridge between Two Distant Illnesses

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