<i>Toxoplasma</i>histone acetylation remodelers as novel drug targets

Vanagas, Laura; Jeffers, Victoria; Bogado, Silvina S.; Dalmasso, Carolina; Sullivan, William J.; Angel, Sérgio O.

doi:10.1586/eri.12.100

Cited by 49 publications

(49 citation statements)

References 110 publications

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“…Consistent with the immunostimulant effect of NSO (Fararh et al 2004), DNA fragmentation and activation of the mitochondrial-signaling proapoptotic pathway may be another modes of action that were previously reported by Salim et al (2013) in their trials for treating cancer cells with NSO. Moreover, NSO can inhibit DNA synthesis by inhibiting histone deacetylase (HDAC) enzyme in cancer cells (Vanagas et al 2012;Zubair et al 2013), a mode of action that needs further verification with respect to Toxoplasma.…”

Section: Discussionmentioning

confidence: 99%

Effect of Nigella sativa oil on experimental toxoplasmosis

2015

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Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii protozoon. It is most commonly treated by pyrimethamine (PYR); however, this was intolerable by many patients. The aim of this study was to assess therapeutic effects of Nigella sativa oil (NSO) alone and combined with pyrimethamine (PYR) compared to a previous combination of clindamycin (CLN) and (PYR). One hundred Albino mice were used in the current study and were equally divided into five groups: normal (I), infected untreated control (II); infected, treated with NSO-only (III); infected, treated with NSO + PYR (IV); and infected, treated with CLN + PYR (V). The virulent RH Toxoplasma strain was used in infection survival rates estimation, impression smears from liver and spleen, and histopathological and ultrastructural studies were done. Liver malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined. Interferon-γ and specific IgM were also measured in sera by ELISA. Results showed that NSO alone has no direct anti-Toxoplasma effect, whereas its combination with PYR produced potent effect that is comparable to CLN + PYR. It significantly increased the survival rate and decreased the parasite density and pathological insult in both liver and spleen. Also, significant increase in interferon-γ level denotes stimulation of cellular immunity. NSO + PYR combination markedly improved the antioxidant capacity of Toxoplasma infected mice compared to the infected untreated ones and to CLN/PYR. In conclusion, although NSO, if administered alone, has significant immunostimulant and antioxidant properties, it failed to decrease tachyzoite counts. Combination of NSO and PYR had synergistic effect in treatment of toxoplasmosis.

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Section: Discussionmentioning

confidence: 99%

Effect of Nigella sativa oil on experimental toxoplasmosis

2015

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“…FR23522 and its derivatives also display potent activity against Toxoplasma by targeting a KDAC called TgHDAC3 (4,5). In contrast, there are no reports to date of a Toxoplasma KAT inhibitor despite genetic studies showing that KATs are essential for parasite viability (6)(7)(8)(9)(10)(11)(12)(13). The putative KAT inhibitor MC1626 has inhibitory activity against tachyzoites but most likely through an off-target effect (14).…”

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confidence: 99%

Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

Jeffers

Gao

Checkley

et al. 2016

Antimicrob Agents Chemother

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Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasite Toxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required for Toxoplasma tachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibits Toxoplasma tachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibits Plasmodium falciparum asexual replication with a 50% inhibitory concentration (IC 50 ) similar to that for Toxoplasma. Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication.

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“…As seen for higher eukaryotic cells, the Toxoplasma acetylome contains proteins residing in all cellular compartments, including the single parasite mitochondrion. Lysine acetylation is critical for parasite replication and survival, and enzymes modulating lysine acetylation have been validated as drug targets (12)(13)(14). We have characterized a number of KATs in the parasite, noting that TgGCN5 family KATs are exclusively nuclear and TgMYST family KATs are predominantly cytosolic (15)(16)(17).…”

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confidence: 99%