Department of Biochemistry, Genetics and Microbiology, Institute for Sustainable Malaria Control, University of Pretoria, Private Bag x20, Hatfield, 0028, South Africa.
Sci Rep. 2020 Feb 11;10(1):2355. doi: 10.1038/s41598-020-59298-4.
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 non-histone 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.
疟原虫（Plasmodium falciparum）的表观基因组与寄生虫各种重要过程的调控有关，包括无性发育过程中的增殖控制以及有性分化的控制。表观基因组的独特性质促使人们研究是否有可能利用新型化学型靶向表观遗传调节剂。在这里，我们研究了针对癌细胞中各种表观遗传修饰剂具有活性的 95 种化合物库的多样性，以研究它们对疟原虫不同发育阶段的活性。我们表明，在无性和有性发育过程中，疟原虫对表观遗传扰动的敏感性不同，早期配子体对靶向组蛋白和非组蛋白表观遗传修饰剂的 epi 药物特别敏感。此外，5 种靶向组蛋白乙酰化和甲基化的化合物对无性寄生虫、早期和晚期配子体具有强大的多阶段活性，具有阻断传播的潜力。总的来说，这些结果证明了这些命中化合物具有抗疟潜力，值得进一步研究。
