5vr4
RNA octamer containing 2'-F-4'-OMe U.
Structural highlights
Publication Abstract from PubMedWe designed novel 4'-modified 2'-deoxy-2'-fluorouridine (2'-F U) analogues with the aim to improve nuclease resistance and potency of therapeutic siRNAs by introducing 4'-C-methoxy (4'-OMe) as the alpha (C4'alpha) or beta (C4'beta) epimers. The C4'alpha epimer was synthesized by a stereoselective route in six steps; however, both alpha and beta epimers could be obtained by a non-stereoselective approach starting from 2'-F U. 1H-NMR analysis and computational investigation of the alpha-epimer revealed that the 4'-OMe imparts a conformational bias towards the North-East sugar pucker, due to intramolecular hydrogen bonding and hyperconjugation effects. The alpha-epimer generally conceded similar thermal stability as unmodified nucleotides, whereas the beta-epimer led to significant destabilization. Both 4'-OMe epimers conferred increased nuclease resistance, which can be explained by the close proximity between 4'-OMe substituent and the vicinal 5'- and 3'-phosphate group, as seen in the X-ray crystal structure of modified RNA. siRNAs containing several C4'alpha-epimer monomers in the sense or antisense strands triggered RNAi-mediated gene silencing with efficiencies comparable to that of 2'-F U. 4'-C-Methoxy-2'-Deoxy-2'-Fluoro Modified Ribonucleotides Improve Metabolic Stability and Elicit Efficient RNAi-Mediated Gene Silencing.,Malek-Adamian E, Guenther D, Matsuda S, Martinez-Montero S, Zlatev I, Harp J, Burai Patrascu M, Foster DJ, Fakhoury JJ, Perkins L, Moitessier N, Manoharan R, Taneja N, Bisbe A, Charisse K, Maier MA, Rajeev KG, Egli M, Manoharan M, Damha MJ J Am Chem Soc. 2017 Sep 22. doi: 10.1021/jacs.7b07582. PMID:28937776[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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