2020
DOI: 10.1128/aac.02523-19
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Activity of Epigenetic Inhibitors against Plasmodium falciparum Asexual and Sexual Blood Stages

Abstract: Earlier genetic and inhibitor studies showed that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new antimalarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

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Cited by 28 publications
(28 citation statements)
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“…Additionally, we assessed the effects of chemically inhibiting histone demethylases (HDMs) on H3K36me2&3 levels and gene expression during early gametocyte development. Using histone methylation pro ling and whole transcriptome analysis, we demonstrate the link between H3K36me2&3 demethylation and the enhanced potency of the panselective Jumonji inhibitor, JIB-04 in gametocytes (37,38). This paper provides the rst association between H3K36me2&3 and gene regulation in gametocytes and con rms the dynamic deposition and removal of such hPTMs during P. falciparum sexual differentiation and development.…”
Section: Introductionmentioning
confidence: 71%
“…Additionally, we assessed the effects of chemically inhibiting histone demethylases (HDMs) on H3K36me2&3 levels and gene expression during early gametocyte development. Using histone methylation pro ling and whole transcriptome analysis, we demonstrate the link between H3K36me2&3 demethylation and the enhanced potency of the panselective Jumonji inhibitor, JIB-04 in gametocytes (37,38). This paper provides the rst association between H3K36me2&3 and gene regulation in gametocytes and con rms the dynamic deposition and removal of such hPTMs during P. falciparum sexual differentiation and development.…”
Section: Introductionmentioning
confidence: 71%
“…Given these differences in histone modifying enzymes between P. falciparum and the piroplasms, we decided to test the susceptibility of B. divergens to a library of epigenetic inhibitors previously screened against P. falciparum 12 . Of the 324 compounds tested, 125 (39%) showed ≥50% inhibition at 10 µM against B. divergens blood stages, of which 46 (14%) retained greater than half-maximal activity at 1 µM (Figure 2A, Supplemental Figure 1 and Table 2, Supplemental Dataset 2).…”
Section: Resultsmentioning
confidence: 99%
“…Intravenous administration during chemotherapy leads to plasma concentration of 5 µM 26 , around 20-fold higher than its EC90 value against B. divergens . We previously determined toxicity of selected compounds against human HepG2 cells 12 . Several compounds displayed only moderate toxicity against HepG2 cells even at 1 µM (Figure 2B).…”
Section: Resultsmentioning
confidence: 99%
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