Journal
BIOCHIMIE
Volume 95, Issue 12, Pages 2385-2391Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2013.08.025
Keywords
MOE; Methylation; RNA interference; NMR
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Funding
- Slovenian Research Agency (ARRS) [P1-0242, J1-4020]
- EU [261863]
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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. (C) 2013 Elsevier Masson SAS. All rights reserved.
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