5VR4

RNA octamer containing 2'-F-4'-OMe U.

Summary for 5VR4

• Entry DOI: 10.2210/pdb5vr4/pdb
• Descriptor: RNA (5'-R(*CP*GP*AP*AP*(UMO)P*UP*CP*G)-3'), COBALT TETRAAMMINE ION (3 entities in total)
• Functional Keywords: rna
• Biological source: synthetic construct
• Total number of polymer chains: 4
• Total formula weight: 10361.37

Authors

Harp, J.M.,Egli, M. (deposition date: 2017-05-10, release date: 2017-10-04, Last modification date: 2023-10-04)

Primary citation

Malek-Adamian, E.,Guenther, D.C.,Matsuda, S.,Martinez-Montero, S.,Zlatev, I.,Harp, J.,Burai Patrascu, M.,Foster, D.J.,Fakhoury, J.,Perkins, L.,Moitessier, N.,Manoharan, R.M.,Taneja, N.,Bisbe, A.,Charisse, K.,Maier, M.,Rajeev, K.G.,Egli, M.,Manoharan, M.,Damha, M.J.
4'-C-Methoxy-2'-deoxy-2'-fluoro Modified Ribonucleotides Improve Metabolic Stability and Elicit Efficient RNAi-Mediated Gene Silencing.
J. Am. Chem. Soc., 139:14542-14555, 2017

PubMed Abstract: We 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'α) or beta (C4'β) epimers. The C4'α epimer was synthesized by a stereoselective route in six steps; however, both α and β epimers could be obtained by a nonstereoselective approach starting from 2'-F U. H NMR analysis and computational investigation of the α-epimer revealed that the 4'-OMe imparts a conformational bias toward the North-East sugar pucker, due to intramolecular hydrogen bonding and hyperconjugation effects. The α-epimer generally conceded similar thermal stability as unmodified nucleotides, whereas the β-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'α-epimer monomers in the sense or antisense strands triggered RNAi-mediated gene silencing with efficiencies comparable to that of 2'-F U.

PubMed: 28937776
DOI: 10.1021/jacs.7b07582

Experimental method

X-RAY DIFFRACTION (1.5 Å)