Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets.

中文翻译：

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抗疟疾天然产物Salinipostin A可以识别参与恶性疟原虫寄生虫脂质代谢的必需α/β丝氨酸水解酶。

Salinipostin A（Sal A）是一种有效的抗疟原虫海洋天然产物，具有不确定的作用机理。使用基于Sal A的基于活性的探针，我们在恶性疟原虫寄生虫中鉴定了其靶标。所有已鉴定的蛋白质均包含α/β丝氨酸水解酶结构域，其中一些对于寄生虫生长至关重要。必需的靶标之一显示出与人单酰基甘油脂肪酶（MAGL）的高度同源性，并且能够加工包括MAGL酰基甘油酯底物的脂质酯。此Sal A靶标被抗肥胖药Orlistat抑制，该药物可破坏脂质代谢。耐药性选择产生的寄生虫仅显示出敏感性的轻微降低，并且在与弓形虫耐药性相关的含PRELI结构域的蛋白中获得了突变。