2′-O-[2-[2-(N, N-dimethylamino)ethoxy]ethyl] modified oligonucleotides: Symbiosis of charge interaction factors and stereoelectronic effects

(Matrix presented) Oligonucleotides with a novel, 2′ -O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2′-O-DMAEOE) modification have been synthesized. This modification, a cationic analogue of the 2′-O-(2-methoxyethyl) (2′-O-MOE) modification, exhibits high binding affinity to target RNA (but not to DNA) and exceptional resistance to nuclease degradation. Analysis of the crystal structure of a self-complementary oligonucleotide containing a single 2′-O-DMAEOE modification explains the importance of charge factors and gauche effects on the observed antisense properties. 2′-O-DMAEOE modified oligonucleotides are ideal candidates for antisense drugs.