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

  • J Am Chem Soc. 2020 Mar 11;142(10):4739-4748. doi: 10.1021/jacs.9b13207.
Qiang Li  1 ,  Jialiang Chen  1 ,  Marko Trajkovski  2  3 ,  Yifei Zhou  1 ,  Chaochao Fan  1 ,  Kuan Lu  1 ,  Pingping Tang  1 ,  Xuncheng Su  1 ,  Janez Plavec  2  3 ,  Zhen Xi  1 ,  Chuanzheng Zhou  1
Affiliations
  • 1. State Key Laboratory of Elemento-Organic Chemistry and Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin 300071, China.
  • 2. Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana, Slovenia.
  • 3. University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, EN-FIST Centre of Excellence, Ljubljana, Slovenia.
PMID: 32067454 DOI: 10.1021/jacs.9b13207
Abstract

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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