Post-transcriptional modification of Plasmodium falciparum histones has an important role in virulence gene regulation. Malmquist et al. synthesized a library of inhibitors targeting the parasite histone lysine methyltransferases and assessed the potential of these inhibitors as novel antimalarial agents. The library was based on a known inhibitor (BIX-01294) of a human methyltransferase. This compound and its derivative, TM2-115, arrested parasite growth, including growth of multidrug-resistant strains. Flow cytometry and culture analysis revealed that the two compounds were active against all parasite blood stages and exhibited a rapid killing effect in vitro, in addition to reducing parasitaemia in infected mice. Importantly, treatment with either compound substantially reduced histone methylation. These new compounds were also selective for parasites over mammalian cells and so could potentially be used as antimalarials.
ORIGINAL RESEARCH PAPER
Malmquist, N. A. et al. Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum. Proc. Natl Acad. Sci. USA 24 Sep 2012 (doi:10.1073/pnas.1205414109)
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Kåhrström, C. Targeting Plasmodium epigenetic regulation. Nat Rev Microbiol 10, 733 (2012). https://doi.org/10.1038/nrmicro2902
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DOI: https://doi.org/10.1038/nrmicro2902