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 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.
ISIS Pharmaceuticals Inc., 2292 Faraday Avenue, Carlsbad, CA 92009, USA and Department of Chemistry,State University of New York, Buffalo, NY 14260-3000, USA. bbaker@isisph.com
B F
BF
Baker
S S
SS
Lot
J
J
Kringel
S
S
Cheng-Flournoy
P
P
Villiet
H M
HM
Sasmor
A M
AM
Siwkowski
L L
LL
Chappell
J R
JR
Morrow
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005063:Europium / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D009942:Organometallic Compounds / Q000494:pharmacology*; D012315:RNA Caps / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D009942:Organometallic Compounds; D012315:RNA Caps; D018799:Intercellular Adhesion Molecule-1; D005063:Europium