2. Academic Validation
  3. 4'-C-Methoxy-2'-deoxy-2'-fluoro Modified Ribonucleotides Improve Metabolic Stability and Elicit Efficient RNAi-Mediated Gene Silencing

4'-C-Methoxy-2'-deoxy-2'-fluoro Modified Ribonucleotides Improve Metabolic Stability and Elicit Efficient RNAi-Mediated Gene Silencing

  • J Am Chem Soc. 2017 Oct 18;139(41):14542-14555. doi: 10.1021/jacs.7b07582.
Elise Malek-Adamian 1,  Dale C Guenther 2,  Shigeo Matsuda 2,  Saúl Martínez-Montero 1,  Ivan Zlatev 2,  Joel Harp 3,  Mihai Burai Patrascu 1,  Donald J Foster 2,  Johans Fakhoury 1,  Lydia Perkins 2,  Nicolas Moitessier 1,  Rajar M Manoharan 2,  Nate Taneja 2,  Anna Bisbe 2,  Klaus Charisse 2,  Martin Maier 2,  Kallanthottathil G Rajeev 2,  Martin Egli 3,  Muthiah Manoharan 2,  Masad J Damha 1
Affiliations

Affiliations

  • 1 Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.
  • 2 Alnylam Pharmaceuticals , 300 Third Street, Cambridge, Massachusetts 02142, United States.
  • 3 Department of Biochemistry, School of Medicine, Vanderbilt University , Nashville, Tennessee 37232, United States.
PMID: 28937776 DOI: 10.1021/jacs.7b07582
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. 1H 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.

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