Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.

尽管青蒿素联合疗法已成功减轻了全球疟疾负担，但最致命的疟原虫恶性疟原虫的多重耐药性正在全球范围内出现。迫切需要能够杀死疟原虫生命周期所有阶段的创新抗疟药物。在这里，我们报告了化合物 JX21108 的发现，该化合物对疟疾寄生虫的多个生命周期阶段具有广泛的抗疟原虫活性。 JX21108是通过组蛋白脱乙酰酶抑制剂quisinostat的化学优化而开发的。我们确定恶性疟原虫组蛋白脱乙酰酶 1 (PfHDAC1)（一种对寄生虫生长和入侵至关重要的表观遗传调节因子）作为 JX21108 的分子靶点。 PfHDAC1敲低导致重要寄生虫基因下调，这与 JX21108 治疗诱导的转录组变化高度一致。总的来说，我们的数据支持 PfHDAC1 是克服多药耐药性的潜在药物靶点，并且 JX21108 可以治疗疟疾并同时阻止寄生虫传播。