Oligonucleotide-europium complex conjugate designed to cleave the 5 ' cap structure of the ICAM-1 transcript potentiates antisense activity in cells

The 5' cap structure of mRNA is a N7 methylated guanosine residue that is l inked by a 5'-5' triphosphate linkage to the 5'-terminus of cellular and vi ral RNAs synthesized by RNA polymerase II. This unique structure facilitate s several processes of mRNA metabolism, including splicing, nucleocytoplasm ic transport, initiation of translation, and degradation, Previous research has demonstrated that the lanthanide macrocycle complex, Eu(THED)(3+), eff ectively cleaves the 5' cap structure of mRNA in solution by nucleophilic a ttack of the triphosphate linkage via the metal-activated hydroxyethyl grou p of the THED ligand, This report shows that attachment of a Eu(THED)(3+) a nalog 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-treated e ndothelial cells.