Activity of epigenetic inhibitors against <i>Plasmodium falciparum</i> asexual and sexual blood stages

Vanheer, Leen N.; Kafsack, Björn F.C.

doi:10.1101/694422

Cited by 6 publications

(9 citation statements)

References 20 publications

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“…If the P. falciparum homologues of HDACs and HKMTs are indeed targeted by these inhibitors, the finding supports the known importance of histone acetylation and methylation for parasite gene control and survival 20,21 . This is in concordance with a similar study recently released in preprint form 37 . Hydroxamate-based HDACi and 4-quinazolinamine-based HKMTi remained the most potent chemical scaffolds that target Plasmodium parasite development at the symptomatic asexual and transmissible gametocyte forms.…”

Section: Discussionsupporting

confidence: 93%

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Coetzee

Grüning

Opperman

et al. 2020

Sci Rep

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The epigenome of the malaria parasite, Plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of proliferation during asexual development as well as control of sexual differentiation. The unusual nature of the epigenome has prompted investigations into the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity within a library of 95 compounds, active against various epigenetic modifiers in cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during both asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and nonhistone epigenetic modifiers. Moreover, 5 compounds targeting histone acetylation and methylation show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds. The almost inevitable development of drug resistance in malaria parasites enforces continued discovery of novel classes of antimalarial compounds 1. To contribute to global malaria elimination strategies, such compounds would need to target multiple life cycle stages of the parasite 2. This includes targeting the rapidly dividing (~48 h) asexual parasites to reduce parasite burden, as well as targeting mature, terminally differentiated sexual gametocytes to block onward human-to-mosquito transmission of the parasite, or exo-erythrocytic liver stage development to block mosquito-to-human transmission. Importantly, to prolong or prevent resistance development, new chemical matter should target novel biological activities in the parasite 3. In oncology research, epigenetic therapeutics ('epi-drugs') evidently hold great promise as targets for anticancer therapies 4 , with several drugs approved for clinical use, including Azacitidine, Decitabine, Vorinostat and Romidepsin 5. The antitumor activity is ascribed to epigenetic deregulation as a result of inhibition of epigenetic modulators, including histone modifying enzymes and DNA methyltransferases. This results in particular changes in histone post-translational modifications (PTMs), disruption of transcriptional processes, chromatin structure maintenance and DNA repair 6,7. Plasmodium falciparum relies heavily on epigenetic mechanisms to drive both asexual proliferation and sexual differentiation (reviewed in 8-11). The parasite's genome encodes a unique complement of histone modifying enzymes including histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs, including lysine HKMT), protein arginine methyltransferases (PRMTs), and histone demethylases (HDMs) 12 in addition to other non-histone epigenetic modifiers. As a result, inhibitors of histone modifying enzymes have been investigated as no...

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Section: Discussionsupporting

confidence: 93%

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Coetzee

Grüning

Opperman

et al. 2020

Sci Rep

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“…S1a). Some of these compounds' antiplasmodial activity has already been reported by previous works 35,38 . Eleven out of 64 compounds showed strong inhibitory activities on parasite growth (> 90% inhibition) at 500 nM.…”

Section: Discovery Of a New Antimalarial Compoundsupporting

confidence: 57%

“…There are five putative HDACs in P. falciparum; PfHDAC1 (PF3D7_0925700) is the only class I HDAC representative in P. falciparum, while PfHDA1 (PF3D7_1472200) and PfHDA2 (PF3D7_1008000) belong to class II HDACs, and PfSir2a (PF3D7_1328800) and PfSir2b (PF3D7_1451400) are phylogenetically close to class III HDACs 47 . Several HDAC inhibitors with in vitro and in vivo antiplasmodial activity have been reported previously [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]37,38,[57][58][59][60][61] . For instance, WR301801 was discovered via chemical modification based on the structure of SAHA and can inhibit the growth of plasmodial at a low-nanomolar range in vitro, and the selectivity index is about 1000.…”

Section: Discussionmentioning

confidence: 99%

A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

Huang

Tang

et al. 2020

Cell Discov

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Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.

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“…With the exception of tubastatin A, the HDAC inhibitors investigated have been previously tested for in vitro growth inhibition against P. falciparum 3D7 and are active in the nanomolar to micromolar range ( Andrews et al, 2008 ; Engel et al, 2015 ) ( Table 1 ). The activity of tubastatin A at 1 μM has been previously reported ( Vanheer et al, 2020 ); in this study we determined that tubastatin A has an in vitro P. falciparum 3D7 IC 50 of 150 nM ( ±30 nM) ( Table 1 ).…”

Section: Resultssupporting

confidence: 65%

An ELISA method to assess HDAC inhibitor-induced alterations to P. falciparum histone lysine acetylation

Hesping

Skinner‐Adams

Fisher

et al. 2020

International Journal for Parasitology: Drugs and Drug Resistan

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The prevention and treatment of malaria requires a multi-pronged approach, including the development of drugs that have novel modes of action. Histone deacetylases (HDACs), enzymes involved in post-translational protein modification, are potential new drug targets for malaria. However, the lack of recombinant P. falciparum HDACs and suitable activity assays, has made the investigation of compounds designed to target these enzymes challenging. Current approaches are indirect and include assessing total deacetylase activity and protein hyperacetylation via Western blot. These approaches either do not allow differential compound effects to be determined or suffer from low throughput. Here we investigated dot blot and ELISA methods as new, higher throughput assays to detect histone lysine acetylation changes in P. falciparum parasites. As the ELISA method was found to be superior to the dot blot assay using the control HDAC inhibitor vorinostat, it was used to evaluate the histone H3 and H4 lysine acetylation changes mediated by a panel of six HDAC inhibitors that were shown to inhibit P. falciparum deacetylase activity. Vorinostat, panobinostat, trichostatin A, romidepsin and entinostat all caused an ~3-fold increase in histone H4 acetylation using a tetra-acetyl lysine antibody. Tubastatin A, the only human HDAC6-specific inhibitor tested, also caused H4 hyperacetylation, but to a lesser extent than the other compounds. Further investigation revealed that all compounds, except tubastatin A, caused hyperacetylation of the individual N-terminal H4 lysines 5, 8, 12 and 16. These data indicate that tubastatin A impacts P. falciparum H4 acetylation differently to the other HDAC inhibitors tested. In contrast, all compounds caused hyperacetylation of histone H3. In summary, the ELISA developed in this study provides a higher throughput approach to assessing differential effects of antiplasmodial compounds on histone acetylation levels and is therefore a useful new tool in the investigation of HDAC inhibitors for malaria.

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Activity of epigenetic inhibitors against Plasmodium falciparum asexual and sexual blood stages

Cited by 6 publications

References 20 publications

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

An ELISA method to assess HDAC inhibitor-induced alterations to P. falciparum histone lysine acetylation

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