In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

Zhang, Qingqing; Li, Haiming; Huang, Cong; Qu, Yi

doi:10.3389/fcimb.2022.1002817

Cited by 4 publications

(1 citation statement)

References 42 publications

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“…In T. gondii, it has been shown that the reversible acetylation process, mediated by lysine acetyltransferases (KAT) and lysine deacetyl transferases (KDAC), can be excellent therapeutic targets [123]. Among the KDAC inhibitors, also called histone deacetyl transferases, identified are apicidin, FR235222, hydroxamate-based compounds, panobinostat, JF363, tubastatin, SAHA, and MC1742 [124][125][126][127][128][129][130]. Additionally, a KDAC activator, resveratrol, has been described [131].…”

Section: Acetylomementioning

confidence: 99%

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Deng,

Vanagas,

Alonso

et al. 2023

Pathogens

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Toxoplasma gondii, a protozoan parasite with the ability to infect various warm-blooded vertebrates, including humans, is the causative agent of toxoplasmosis. This infection poses significant risks, leading to severe complications in immunocompromised individuals and potentially affecting the fetus through congenital transmission. A comprehensive understanding of the intricate molecular interactions between T. gondii and its host is pivotal for the development of effective therapeutic strategies. This review emphasizes the crucial role of proteomics in T. gondii research, with a specific focus on host–parasite interactions, post-translational modifications (PTMs), PTM crosstalk, and ongoing efforts in drug discovery. Additionally, we provide an overview of recent advancements in proteomics techniques, encompassing interactome sample preparation methods such as BioID (BirA*-mediated proximity-dependent biotin identification), APEX (ascorbate peroxidase-mediated proximity labeling), and Y2H (yeast two hybrid), as well as various proteomics approaches, including single-cell analysis, DIA (data-independent acquisition), targeted, top-down, and plasma proteomics. Furthermore, we discuss bioinformatics and the integration of proteomics with other omics technologies, highlighting its potential in unraveling the intricate mechanisms of T. gondii pathogenesis and identifying novel therapeutic targets.

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Section: Acetylomementioning

confidence: 99%

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Deng,

Vanagas,

Alonso

et al. 2023

Pathogens

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Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity

Boissavy,

Rotili,

Mouveaux

et al. 2023

Antimicrob Agents Chemother

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Toxoplasmosis is a critical health issue for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii that is found worldwide. Although efficient drugs are commonly used to treat toxoplasmosis, serious adverse events are common. Therefore, new compounds with potent anti- T . gondii activity are needed to provide better suited treatments. We have tested compounds designed to target specifically histone deacetylase enzymes. Among the 55 compounds tested, we identified three compounds showing a concentration of drug required for 50% inhibition (IC 50 ) in the low 100 nM range with a selectivity index of more than 100. These compounds are not only active at inhibiting the growth of the parasite in vitro but also at preventing some of the consequences of the acute disease in vivo . Two of these hydroxamate based compound also induce a hyper-acetylation of the parasite histones while the parasitic acetylated tubulin level remains unchanged. These findings suggest that the enzymes regulating histone acetylation are potent therapeutic targets for the treatment of acute toxoplasmosis.

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Histone deacetylase 2 and 3 of Sarcoptes scabiei : characterization of a potential drug target

He,

Xu,

Guo

et al. 2024

Microbiol Spectr

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Scabies is a contagious zoonotic parasitic disease that causes a substantial risk to both human and animal health and results in significant financial losses. No vaccine is available for scabies, and drug resistance to the conventional treatment for the disease has increased. Histone deacetylase (HDAC) modifies proteins by removing acetyl moieties from histones, regulates transcription, and is crucial for the immune system and apoptotic processes. This study aimed to clone, express, and determine the immunoreactivity of HDAC-2 and HDAC-3 of scabies mites to investigate their potential as scabies drug targets. The effects of inhibitors on recombinant Sarcoptes scabiei HDAC-2 (rSsHDAC-2) and rSsHDAC-3, as well as on the survival rate and ultrastructure of scabies mites in vitro , were also verified. The findings showed that the inhibitors reduced the acetylase activity of rSsHDAC-2 and rSsHDAC-3. Additionally, these inhibitors could significantly reduce the survival rate of scabies mites, making structural alterations in the mites such as mitochondrial pyknosis and cytoplasmic vacuoles and reaching a fatality rate of 76.7% after 24 h of action. In conclusion, HDAC-2 and HDAC-3 were critical to the survival of scabies mites and might be targeted by medications. Furthermore, the effect of inhibitors on the survival rate and structure of isolated scabies mites provides a new direction for developing therapeutic drugs for scabies. IMPORTANCE In this study, we successfully cloned and expressed recombinant SsHDAC-2 and SsHDAC-3 in a prokaryotic system and confirmed their acetylation-deacetylase activities. These results provide a solid experimental foundation for subsequent research on SsHDAC-2 and SsHDAC-3. Furthermore, we report for the first time the use of SsHDAC-2 and SsHDAC-3 as drug targets. We demonstrated that the inhibition of these HDACs by pharmacological agents can lead to structural damage in the parasite, thereby impacting the survival activity of the scabies mite. This finding opens up a novel therapeutic avenue for the treatment of scabies.

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In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

Cited by 4 publications

References 42 publications

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Proteomics Applications in Toxoplasma gondii: Unveiling the Host–Parasite Interactions and Therapeutic Target Discovery

Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity

Histone deacetylase 2 and 3 of Sarcoptes scabiei : characterization of a potential drug target

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