Abstract:
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.
