title: NMR structure of 2'-O-(2-methoxyethyl) modified and C5-methylated RNA dodecamer duplex.
abstract: The solution-state structure of 2'-O-(2-methoxyethly) substituted dodecamer r(*CG*CGAA*U*U*CG*C)d(G), 2'-MOE RNA, with all cytosines and uracils methylated at the C5-position has been determined by NMR spectroscopy. The chemical modifications were used to improve the oligonucleotide's drug-like properties. The 2'-MOE group drives pseudorotational equilibrium of the ribofuranose moiety to the N-type conformation and supposedly results in structural preorganization leading to high affinity of a modified oligonucleotide towards its complementary biological target, improved pharmacokinetic and toxicological properties. The high melting temperature of the antiparallel duplex structure adopted by 2'-MOE RNA was explained through the formation of a stable A-form RNA consistent with effective base-pairing and stacking interactions. The comparison of the solution-state structure with the crystal structure of a non-methylated analogue shows an increase in the stacking at the base pair steps for the C5-methylated 2'-MOE RNA duplex. The MOE substituents adopt a well-defined structure in the minor groove with the predominant gauche conformations around the ethylene bond.
authors.affiliation: Krka, d.d., Šmarješka cesta 6, 8501 Novo mesto, Slovenia.
authors.forename: Miha
authors.initials: M
authors.lastname: Plevnik
authors.forename: Mirko
authors.initials: M
authors.lastname: Cevec
authors.forename: Janez
authors.initials: J
authors.lastname: Plavec
mesh_terms: D020029:Base Pairing; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D009843:Oligoribonucleotides / Q000737:chemistry*
chemical_list: C119446:2'-O-(2-methoxyethyl)-RNA; D009843:Oligoribonucleotides
keywords: 2′-MOE; 2′-O-(2-methoxyethly); DQF-COSY; MOE; Methylation; NMR; NOESY; RNA interference; T(m); double-quantum filtered correlation spectroscopy; melting temperature; nuclear Overhauser effect spectroscopy; nuclear magnetic resonance; r.m.s.d.; root mean square deviation