NMR structure of 2′-O-(2-methoxyethyl) modified and C5-methylated RNA dodecamer duplex |
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Authors: | Miha Plevnik Mirko Cevec Janez Plavec |
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Affiliation: | 1. Krka, d.d., Šmarješka cesta 6, 8501 Novo mesto, Slovenia;2. Slovenian NMR Center, National Institute of Chemistry, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia;3. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ašker?eva cesta 5, 1000 Ljubljana, Slovenia;4. EN-FIST Center of Excellence, Dunajska cesta 156, 1000 Ljubljana, Slovenia |
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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. |
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Keywords: | MOE Methylation RNA interference NMR |
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