Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA.
2'-O-(2-Methoxyethyl)-RNA (MOE-RNA) is a nucleic acid analog with promising features for antisense applications. Compared with phosphorothioate DNA (PS-DNA), the MOE modification offers improved nuclease resistance, enhanced RNA affinity, improved cellular uptake and intestinal absorption, reduced toxicity and immune stimulation. The crystal structure of a fully modified MOE-RNA dodecamer duplex (CGCGAAUUCGCG) was determined at 1.7 A resolution. In the majority of the MOE substituents, the torsion angle around the ethylene alkyl chain assumes a gauche conformation. The conformational preorganization of the MOE groups is consistent with the improved RNA affinity and the extensive hydration of the substituents could play a role in the improved cellular uptake of MOE-RNA. A specific hydration pattern that bridges substituent and phosphate oxygen atoms in the minor groove of MOE-RNA may explain its high nuclease resistance.
Teplova
M
M
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Minasov
G
G
Tereshko
V
V
Inamati
G B
GB
Cook
P D
PD
Manoharan
M
M
Egli
M
M
D020029:Base Pairing; D001483:Base Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D005030:Ethylenes / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides; D010100:Oxygen / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D016372:RNA, Antisense / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014867:Water / Q000378:metabolism
C119446:2'-O-(2-methoxyethyl)-RNA; D005030:Ethylenes; D009843:Oligoribonucleotides; D010710:Phosphates; D016372:RNA, Antisense; D014867:Water; C036216:ethylene; D010100:Oxygen