Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A
Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A
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DOI：
10.1038/nchembio776
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发表时间：
2006-04-01
影响因子：
14.8
通讯作者：
Pelletier, J
中科院分区：
文献类型：
--
作者：
Bordeleau, ME;Mori, A;Pelletier, J
RNA解旋酶是一种分子马达，几乎参与了RNA代谢的所有方面。真核起始因子（eIF） 4A是DEAD-box RNA解旋酶家族的典型成员。它被认为是利用ATP水解产生的能量来解开mRNA结构，并与其他翻译因子一起，在翻译起始阶段为核糖体募集准备mRNA模板。在筛选新的真核生物翻译起始抑制剂的海洋提取物中，我们鉴定了天然产物马嘌呤醇。我们在这里表明，该化合物是一种选择性和有效的eIF4A rna结合活性抑制剂，可用于区分体外和体内eIF4A依赖和非依赖的翻译起始模式。我们还表明，当感染细胞暴露于马嘌呤醇时，脊髓灰质炎病毒的复制被延迟。我们的研究证明了用小分子抑制剂选择性靶向DEAD-box解旋酶家族成员的可行性。
RNA helicases are molecular motors that are involved in virtually all aspects of RNA metabolism. Eukaryotic initiation factor (eIF) 4A is the prototypical member of the DEAD-box family of RNA helicases. It is thought to use energy from ATP hydrolysis to unwind mRNA structure and, in conjunction with other translation factors, it prepares mRNA templates for ribosome recruitment during translation initiation. In screening marine extracts for new eukaryotic translation initiation inhibitors, we identified the natural product hippuristanol. We show here that this compound is a selective and potent inhibitor of eIF4A RNA-binding activity that can be used to distinguish between eIF4A-dependent and -independent modes of translation initiation in vitro and in vivo. We also show that poliovirus replication is delayed when infected cells are exposed to hippuristanol. Our study demonstrates the feasibility of selectively targeting members of the DEAD-box helicase family with small-molecule inhibitors.