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首页> 外文期刊>EBioMedicine >A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics
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A Class of Diacylglycerol Acyltransferase 1 Inhibitors Identified by a Combination of Phenotypic High-throughput Screening, Genomics, and Genetics

机译：通过表型高通量筛选，基因组学和遗传学的组合确定的一类二酰基甘油酰基转移酶1抑制剂。

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Excess lipid storage is an epidemic problem in human populations. Thus, the identification of small molecules to treat or prevent lipid storage-related metabolic complications is of great interest. Here we screened >320.000 compounds for their ability to prevent a cellular lipid accumulation phenotype. We used fly cells because the multifarious tools available for this organism should facilitate unraveling the mechanism-of-action of active small molecules. Of the several hundred lipid storage inhibitors identified in the primary screen we concentrated on three structurally diverse and potent compound classes active in cells of multiple species (including human) and negligible cytotoxicity. Together with Drosophila in vivo epistasis experiments, RNA-Seq expression profiles suggested that the target of one of the small molecules was diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in the production of triacylglycerols and prominent human drug target. We confirmed this prediction by biochemical and enzymatic activity tests.
机译：过多的脂质储存是人类人群中的流行病。因此，识别用于治疗或预防脂质存储相关的代谢并发症的小分子引起了极大的兴趣。在这里，我们筛选了> 320.000种化合物预防细胞脂质蓄积表型的能力。我们使用了蝇细胞，因为可用于该生物的多种工具应有助于阐明活性小分子的作用机理。在初步筛选中确定的数百种脂质存储抑制剂中，我们集中于在多种物种（包括人）的细胞中活跃且细胞毒性可忽略的三种结构多样且有效的化合物类别。结合果蝇体内上皮实验，RNA-Seq表达谱表明，其中一个小分子的靶标是二酰基甘油酰基转移酶1（DGAT1），这是三酰基甘油生产中的关键酶和重要的人类药物靶标。我们通过生化和酶活性测试证实了这一预测。

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