Synthetic Polyamines to Regulate mRNA Translation through the Preservative Binding of Eukaryotic Initiation Factor 4E to the Cap Structure

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• 作者：Hirokuni Uchida ; Keiji Itaka ; Satoshi Uchida ; Takehiko Ishii ; Tomoya Suma ; Kanjiro Miyata ; Makoto Oba ; Nobuhiro Nishiyama ; Kazunori Kataoka
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：February 10, 2016
• 年：2016
• 卷：138
• 期：5
• 页码：1478-1481
• 全文大小：259K
• ISSN：1520-5126

文摘

Polyion complexes (PICs) of mRNA with synthetic polyamines are receiving increasing attention as mRNA delivery vehicles, and the search for polyamine structure maximizing the translational efficiency of complexed mRNA becomes a critical research topic. Herein, we discovered that fine-tuning of the protonation status of synthetic polyamines can regulate mRNA translation through the preservative binding of eukaryotic initiation factor 4E to m⁷GpppN (cap structure) on the 5′ end of mRNA. A series of polyamines with varied numbers of aminoethylene repeats in their side chains were prepared by an aminolysis reaction of poly(β-benzyl-l-aspartate) and paired with mRNA to form PICs. PICs formed from polyamines with higher numbers of aminoethylene repeats preserved the original translational efficiency to naked mRNA, whereas the efficiency significantly dropped by decreasing the number of aminoethylene repeats in the polyamines. Immunoprecipitation assays using anti-eIF4E antibodies revealed that the binding affinity of eIF4E to the cap structure of mRNA in the PIC was sensitive to the number of charged aminoethylene repeats in the polyamine side chain and was strongly correlated with their translational efficiency. These results indicate that the fine-tuning of the polyamine structure plays a critical role in maximizing the translational efficiency of mRNA in the PICs having potential utility as mRNA delivery vehicles.