Histone Deacetylases As Targets for Antitrypanosomal Drugs

Zuma, Aline Araújo; Souza, Wanderley de

doi:10.4155/fsoa-2018-0037

Cited by 20 publications

(13 citation statements)

References 100 publications

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“…The redirection of drugs already released on the pharmaceutical market is a well-known practice to identify new therapies for neglected parasitic diseases. Histone deacetylase (HDACs) inhibitors are among this group of drugs and were first developed for cancer treatment ( Gelb et al, 2003 ; Nwaka and Hudson, 2006 ), but soon after showed a great variety of effects and perspectives, including anti-protozoan activity ( Zuma et al, 2018 ; Fioravanti et al, 2020 ). HDACs are responsible for post-translational modifications (PTM) controlling the acetylation status of histones, regulating gene expression and leading to cellular growth arrest ( Ruijter et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics

Araújo-Silva

Souza

Martins‐Duarte

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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The redirectioning of drugs in the pharmaceutical market is a well-known practice to identify new therapies for parasitic diseases. The histone deacetylase inhibitors Tubastatin A (TST) and Suberoylanilide Hydroxamic Acid (SAHA), firstly developed for cancer treatment, are effective against protozoa parasites. In this work, we aimed to demonstrate the activity of these drugs as potential agents against Toxoplasma gondii , the causative agent of toxoplasmosis. TST and SAHA were active against different genotypes of Toxoplasma gondii , such as, RH (type I), EGS (I/III) and ME49 (type II) strains. The IC₅₀ values for the RH strain were 19 ± 1 nM and 520 ± 386 nM for TST and 41 ± 3 nM and 67 ± 36 nM for SAHA, for 24 and 48 h, respectively. Both compounds were highly selective for T. gondii and their anti-proliferative effect was irreversible for 8 days. The calculated selectivity indexes (39 for TST and 30 for SAHA) make them lead compounds for the future development of anti- Toxoplasma molecules. Western blotting showed TST led to a significant increase of the nuclear histone H4 and a decrease of H3 acetylation levels. Treatment with 1 μM TST and 0.1 μM SAHA for 48 h decreased the amount of global α-tubulin. Fluorescence and electron microscopy showed that both drugs affected the endodyogeny process impairing the budding of daughter cells. The drugs led to the formation of large, rounded masses of damaged parasites with several centrosomes randomly dispersed and incorrect apicoplast division and positioning. TST-treated parasites showed a rupture of the mitochondrial membrane potential and led to a failure of the IMC assembling of new daughter cells. SAHA and TST possibly inhibit HDAC3 and other cytoplasmic or organelle targeted HDACs involved in the modification of proteins other than histones.

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Section: Introductionmentioning

confidence: 99%

HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics

Araújo-Silva

Souza

Martins‐Duarte

et al. 2021

International Journal for Parasitology: Drugs and Drug Resistan

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“…According to Murphy et al, CTLA-4 blockers enhance host resistance against Leishmania donovani [ 57 ], while the same effects have been observed for PDL-1 blockers by Habib et al [ 58 ]. Histone deacetylase enzymes (HDAC) play a significant role in the modulation of parasites’ gene expression, and hence they could serve as potent targets for HAT therapy [ 59 ]. Many inhibitors of these enzymes (class I/II HDAC inhibitors and sirtuin inhibitors) have been discovered and approved for anticancer therapy.…”

Section: Drug Targets and Inhibitorsmentioning

confidence: 99%

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

et al. 2021

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The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”.

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“…A promising strategy to treat schistosomiasis amongst other parasitic diseases is to target the epigenome of the parasite [ 11 , 12 , 13 ]. Histone modifying proteins have thus emerged as potential targets to modulate the epigenome of this parasite in the hope to treat this parasitic ailment.…”

Section: Introductionmentioning

confidence: 99%

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

et al. 2021

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Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8–inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein–inhibitor BFE, different quantitative structure–activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC50 values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors.

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Histone Deacetylases As Targets for Antitrypanosomal Drugs

Cited by 20 publications

References 100 publications

HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics

HDAC inhibitors Tubastatin A and SAHA affect parasite cell division and are potential anti-Toxoplasma gondii chemotherapeutics

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

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