Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Natural Products LINCHPIN Laboratory and Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, TX 77843, USA.
Biochem Cell Biol. 2020 Aug;98(4):502-510. doi: 10.1139/bcb-2019-0307. Epub 2020 Feb 2.
The natural product pateamineA (PatA) is a highly potent antiproliferative agent. PatA and the simplified analog desmethyl, desamino pateamineA (DMDAPatA) have exhibited cytotoxicity selective for rapidly proliferating cells, and have been shown to inhibit cap-dependent translation initiation through binding to eIF4A (eukaryotic initiation factor 4A) of the eIF4F complex. PatA and DMDAPatA are both known to stimulate the RNA-dependent ATPase, and ATP-dependent RNA helicase activities of eIF4A. The impact of other eIF4F components, eIF4E and eIF4G, on DMDAPatA action were investigated in vitro and in cultured mammalian cells. The perturbation of the eIF4A-eIF4G association was found to be eIF4E- and mRNA cap-dependent. An inhibitory effect on helicase activity of eIF4A was observed when it was part of a complex that mimicked the eIF4F complex. We propose a model of action for DMDAPatA (and by supposition PatA) where the cellular activity of the compound is dependent on an "active" eIF4F complex.
天然产物 pateamineA（PatA）是一种高效的抗增殖剂。PatA 和简化类似物去甲基、去氨基 pateamineA（DMDAPatA）对快速增殖的细胞表现出细胞毒性选择性，并已被证明通过与 eIF4F 复合物中的 eIF4A（真核起始因子 4A）结合来抑制帽依赖性翻译起始。PatA 和 DMDAPatA 都已知能刺激 eIF4A 的 RNA 依赖性 ATP 酶和 ATP 依赖性 RNA 解旋酶活性。在体外和培养的哺乳动物细胞中研究了其他 eIF4F 成分，即 eIF4E 和 eIF4G，对 DMDAPatA 作用的影响。发现干扰 eIF4A-eIF4G 缔合是 eIF4E 和 mRNA 帽依赖性的。当 eIF4A 作为模拟 eIF4F 复合物的复合物的一部分时，观察到对其解旋酶活性的抑制作用。我们提出了 DMDAPatA（和假定的 PatA）的作用模型，其中化合物的细胞活性依赖于“活性”eIF4F 复合物。
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