Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
Division of Infection and Immunity, Walter and Eliza Hall Institute for Medical Research, Parkville, VIC, 3052, Australia.
Nat Commun. 2020 Apr 14;11(1):1780. doi: 10.1038/s41467-020-15440-4.
A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.
咪唑并哌嗪（IZP）类化合物是一种很有前途的新型抗疟药物。IZP 类化合物 KAF156（Ganaplacide）和 GNF179 对疟原虫有性血期感染具有治疗作用，能在动物模型中预防传播和阻断感染。但尽管已经确定了恶性疟原虫中的耐药机制，IZP 的作用模式仍不清楚。在这里，我们将酿酒酵母中的体外进化和基因组分析与恶性疟原虫中的分子、代谢组学和化学生物学方法相结合，进行了研究。我们的研究结果表明，IZP 耐药的酿酒酵母克隆携带与内质网（ER）脂质平衡和自噬相关基因的突变。在疟原虫中，IZP 抑制蛋白质运输，阻断新渗透途径的建立，并导致内质网扩张。我们的数据突出了一种与用于治疗疟疾的标准化合物不同的阻断寄生虫发育的机制，并证明了 IZP 用于研究 ER 依赖的蛋白质加工的潜力。
