2. Academic Validation
  3. A 2'-modified uridine analog, 2'-O-(methylthiomethoxy)methyl uridine, for siRNA applications

A 2'-modified uridine analog, 2'-O-(methylthiomethoxy)methyl uridine, for siRNA applications

  • Bioorg Med Chem Lett. 2022 Oct 15;74:128939. doi: 10.1016/j.bmcl.2022.128939.
Fangjie Lyu 1,  Seongjin An 2,  Yoshiaki Kobayashi 3,  Kohei Nomura 1,  Rintaro Baba 1,  Naoko Abe 1,  Haruka Hiraoka 1,  Fumitaka Hashiya 4,  Zhaoma Shu 1,  Kumiko Ui-Tei 5,  Yasuaki Kimura 1,  Hiroshi Abe 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan.
  • 3 Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
  • 4 Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan.
  • 5 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
  • 6 Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan; Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan; CREST, Japan Science and Technology Agency, 7, Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan. Electronic address: h-abe@chem.nagoya-u.ac.jp.
PMID: 35964844 DOI: 10.1016/j.bmcl.2022.128939
Abstract

The medicinal applications of siRNAs have been intensively examined but are still hindered by their low molecular stability under biological conditions and off-target effects, etc. The introduction of chemical modifications to the nucleoside is a promising strategy for solving these limitations. Herein, we describe the development of a new uridine analog, U*, that has a (methylthiomethoxy)methoxy group at the 2' position. The phosphoramidite reagent corresponding to U* was easily synthesized and the RNA Oligonucleotides containing U* were stably prepared using a standard protocol for oligonucleotide synthesis. The introduction of U* into the siRNA resulted in positive or negative effects on the targeted gene silencing in a position-dependent manner, and the positive effects were attributed to the improved stability under biological conditions. The thermodynamic analysis of the U*-modified RNAs revealed a slight destabilization of the dsRNA, based depending on which U was strategically utilized to restrain the off-target effects of the siRNA. This study describes a rare example of nucleoside analogs with a large substitution at the 2'-position in the context of an siRNA application and is informative for the development of other analogs to further improve the molecular properties of siRNAs for medicinal applications.

Keywords

Chemical modification; Modified nucleoside; Off-target effect; Stability; siRNA.

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