Drug target discovery in human malaria; inhibition of histone deacetylases (HDAC) in Plasmodium falciparum.

Abstract

The emergence of drug-resistance Plasmodium falciparum to the current chemotherapies indicates an urgent need to discover new drug target for malarial control. The intricate transcriptome of the intraerythrocytic developmental cycle (IDC) of Plasmodium falciparum raises many questions about the mechanisms in regulating the transcription. It has been suggested that epigenetic regulation plays an important role in regulating the gene expression throughout Plasmodium life cycle in a just-in-time manner. A number of histone modifying enzymes in Plasmodium falciparum have been identified. To understand the effects of histone deacetylase (HDAC) inhibitors on histone modification, Plasmodium falciparum cells were treated with different HDAC inhibitors at various IDC stages and western hybridization was carried out. The two HDAC inhibitors used in this study were apicidin (API) and Trichostatin A (TSA); both HDAC inhibitors have shown to affect the level of acetylation on H3 and H4 modification. Interestingly, the level of methylated H3K4 and H4K20 seems to be altered by API and TSA. Taken together, the effect of HDAC inhibitor has a profound effect on the epigenome of Plasmodium falciparum. This suggests that histone modifying enzyme could be a promising target for anti-malarial chemotherapy. Therefore, further transcriptional response studies are necessary to affirm the effect of HDAC inhibitor in the transcriptome level with regards to the effect of HDAC inhibitor in the epigenome level.