안성진 (The University of Tokyo)

한빛사논문

조회231

The University of Tokyo

CV File 80 kb

Nucleic Acids Res., Sep 05 2024, gkae741 | https://doi.org/10.1093/nar/gkae741 Synthesis of 2'-formamidonucleoside phosphoramidites for suppressing the seed-based off-target effects of siRNAs

Kohei Nomura^1,†, Seongjin An^2,†, Yoshiaki Kobayashi³, Jiro Kondo⁴, Ting Shi¹, Hirotaka Murase¹, Kosuke Nakamoto¹, Yasuaki Kimura¹, Naoko Abe¹, Kumiko Ui-Tei^2,3 and Hiroshi Abe^1,5,6,7,*

¹Department of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan

²Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan

³Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan

⁴Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioi-cho, Chiyoda-ku 102-8554 Tokyo, Japan

⁵Research Center for Materials Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan

⁶CREST, Japan Science and Technology Agency, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan

⁷Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi464-8601, Japan

^*To whom correspondence should be addressed.: Hiroshi Abe

^†The first two authors should be regarded as Joint First Authors.

Abstract

In this study, we report the synthesis of 2'-formamidonucleoside phosphoramidite derivatives and their incorporation into siRNA strands to reduce seed-based off-target effects of small interfering RNAs (siRNAs). Formamido derivatives of all four nucleosides (A, G, C and U) were synthesized in 5-11 steps from commercial compounds. Introducing these derivatives into double-stranded RNA slightly reduced its thermodynamic stability, but X-ray crystallography and CD spectrum analysis confirmed that the RNA maintained its natural A-form structure. Although the introduction of the 2'-formamidonucleoside derivative at the 2nd position in the guide strand of the siRNA led to a slight decrease in the on-target RNAi activity, the siRNAs with different sequences incorporating 2'-formamidonucleoside with four kinds of nucleobases into any position other than 2nd position in the seed region revealed a significant suppression of off-target activity while maintaining on-target RNAi activity. This indicates that 2'-formamidonucleosides represent a promising approach for mitigating off-target effects in siRNA therapeutics.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-06)
연구진국외 연구진
분야 생명과학 > 분자생물학

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