Bordeleau Marie-Eve, Mori Ayaka, Oberer Monika, Lindqvist Lisa, Chard Louisa S, Higa Tatsuo, Belsham Graham J, Wagner Gerhard, Tanaka Junichi, Pelletier Jerry
Department of Biochemistry, McIntyre Medical Sciences Building Rm. 810, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Nat Chem Biol. 2006 Apr;2(4):213-20. doi: 10.1038/nchembio776. Epub 2006 Mar 12.
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.
RNA解旋酶是一类分子马达，几乎参与RNA代谢的各个方面。真核生物起始因子（eIF）4A是RNA解旋酶DEAD-box家族的典型成员。它被认为利用ATP水解产生的能量解开mRNA结构，并与其他翻译因子一起，在翻译起始过程中为核糖体招募准备mRNA模板。在筛选海洋提取物寻找新型真核生物翻译起始抑制剂时，我们鉴定出了天然产物马尿酸甾醇。我们在此表明，该化合物是eIF4A RNA结合活性的选择性强效抑制剂，可用于在体外和体内区分依赖eIF4A和不依赖eIF4A的翻译起始模式。我们还表明，当感染脊髓灰质炎病毒的细胞暴露于马尿酸甾醇时，病毒复制会延迟。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。
