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4′-Fluorinated RNA: Synthesis, Structure, and Applications as a Sensitive 19F NMR Probe of RNA Structure and Function

  • Qiang Li
    Qiang Li
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Qiang Li
  • Jialiang Chen
    Jialiang Chen
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
  • Marko Trajkovski
    Marko Trajkovski
    Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana, Slovenia
    University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, EN-FIST Centre of Excellence, Ljubljana, Slovenia
  • Yifei Zhou
    Yifei Zhou
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Yifei Zhou
  • Chaochao Fan
    Chaochao Fan
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Chaochao Fan
  • Kuan Lu
    Kuan Lu
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Kuan Lu
  • Pingping Tang
    Pingping Tang
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
  • Xuncheng Su
    Xuncheng Su
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Xuncheng Su
  • Janez Plavec*
    Janez Plavec
    Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana, Slovenia
    University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, EN-FIST Centre of Excellence, Ljubljana, Slovenia
    *Email: [email protected] (J.P.)
    More by Janez Plavec
  • Zhen Xi
    Zhen Xi
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    More by Zhen Xi
  • , and 
  • Chuanzheng Zhou*
    Chuanzheng Zhou
    State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China
    *Email: [email protected] (C.Z.)
Cite this: J. Am. Chem. Soc. 2020, 142, 10, 4739–4748
Publication Date (Web):February 18, 2020
https://doi.org/10.1021/jacs.9b13207
Copyright © 2020 American Chemical Society

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    Abstract

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    Fluorinated RNA molecules, particularly 2′-F RNA, have found a wide range of applications in RNA therapeutics, RNA aptamers, and ribozymes and as 19F NMR probes for elucidating RNA structure. Owing to the instability of 4′-F ribonucleosides, synthesis of 4′-F-modified RNA has long been a challenge. In this study, we developed a strategy for synthesizing a 4′-F-uridine (4′FU) phosphoramidite, and we used it to prepare 4′-F RNA successfully. In the context of an RNA strand, 4′FU, which existed in a North conformation, was reasonably stable and resembled unmodified uridine well. The 19F NMR signal of 4′FU was sensitive to RNA secondary structure, with a chemical shift dispersion as large as 4 ppm (compared with <1 ppm for 2′FU), which makes it a valuable probe for discriminating single-stranded RNA and A-type, B-type, and mismatched duplexes. In addition, we demonstrated that because RNA-processing enzymes treated 4′FU the same as unmodified uridine, 4′FU could be used to monitor RNA structural dynamics and enzyme-mediated RNA processing. Taken together, our results indicate that 4′-F RNA represents a probe with wide utility for elucidation of RNA structure and function by means of 19F NMR spectroscopy.

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