Baker B F, Lot S S, Kringel J, Cheng-Flournoy S, Villiet P, Sasmor H M, Siwkowski A M, Chappell L L, Morrow J R
ISIS Pharmaceuticals Inc., 2292 Faraday Avenue, Carlsbad, CA 92009, USA and Department of Chemistry,State University of New York, Buffalo, NY 14260-3000, USA.
Nucleic Acids Res. 1999 Mar 15;27(6):1547-51. doi: 10.1093/nar/27.6.1547.
The 5' cap structure of mRNA is a N7 methylated guanosine residue that is linked by a 5'-5' triphosphate linkage to the 5'-terminus of cellular and viral RNAs synthesized by RNA polymerase II. This unique structure facilitates several processes of mRNA metabolism, including splicing, nucleocytoplasmic transport,initiation of translation, and degradation. Previous research has demonstrated that the lanthanide macrocycle complex, Eu(THED)3+, effectively cleaves the 5' cap structure of mRNA in solution by nucleophilic attack of the triphosphate linkage via the metal-activated hydroxyethyl group of the THED ligand. This report shows that attachment of a Eu(THED)3+analog to the 3'-terminus of an antisense oligonucleotide, which targets the 5'-terminus of the intercellular adhesion molecule 1 mRNA, potentiates the inhibitory activity of the antisense oligonucleotide in cytokine-treatedendothelial cells.
mRNA的5'帽结构是一个N7甲基化鸟苷残基，它通过5'-5'三磷酸键与RNA聚合酶II合成的细胞和病毒RNA的5'-末端相连。这种独特的结构促进了mRNA代谢的几个过程，包括剪接、核质运输、翻译起始和降解。先前的研究表明，镧系大环配合物Eu(THED)3+通过THED配体的金属活化羟乙基对三磷酸键的亲核攻击，有效地在溶液中切割mRNA的5'帽结构。本报告表明，将Eu(THED)3+类似物连接到反义寡核苷酸的3'-末端，该反义寡核苷酸靶向细胞间粘附分子1 mRNA的5'-末端，可增强反义寡核苷酸在细胞因子处理的内皮细胞中的抑制活性。
