2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors

Nucleic Acid Therapeutics
Youngju LeeJaewoo Lee

Abstract

Although the use of RNAs has enormous therapeutic potential, these RNA-based therapies can trigger unwanted inflammatory responses by the activation of pattern recognition receptors (PRRs) and cause harmful side effects. In contrast, the immune activation by therapeutic RNAs can be advantageous for treating cancers. Thus, the immunogenicity of therapeutic RNAs should be deliberately controlled depending on the therapeutic applications of RNAs. In this study, we demonstrated that RNAs containing 2'fluoro (2'F) pyrimidines differentially controlled the activation of PRRs. The activity of RNAs that stimulate toll-like receptors 3 and 7 was abrogated by the incorporation of 2'F pyrimidine. By contrast, incorporation of 2'F pyrimidines enhanced the activity of retinoic acid-inducible gene 1-stimulating RNAs. Furthermore, we found that transfection with RNAs containing 2'F pyrimidine and 5' triphosphate (5'ppp) increased cell death and interferon-β expression in human cancer cells compared with transfection with 2'hydroxyl 5'ppp RNAs, whereas RNAs containing 2'O-methyl pyrimidine and 5'ppp completely abolished the induction of cell death and cytokine expression in the cells. Our findings suggest that incorporation of 2'F and 2'O-meth...Continue Reading

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Citations

Sep 3, 2016·Biochemical and Biophysical Research Communications·Jaewoo LeeBruce A Sullenger
Aug 26, 2017·International Journal of Molecular Sciences·Xiaoqiu WuGe Zhang
Oct 19, 2017·International Journal of Molecular Sciences·Zhenjian ZhuoBaoting Zhang
May 1, 2019·Molecular Diagnosis & Therapy·S K Haßel, G Mayer
Aug 29, 2019·Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology·Sijin GuoPeixuan Guo
Dec 22, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fadwa OdehSaid I Ismail
Feb 1, 2019·Genes·Isabel FreundAlexander H Dalpke
Nov 4, 2016·Nature Reviews. Drug Discovery·Jiehua Zhou, John Rossi
Jul 2, 2019·International Journal of Pharmaceutics·Marimuthu CitartanThean-Hock Tang
Apr 16, 2021·Advanced Drug Delivery Reviews·M Brittany JohnsonKirill A Afonin
May 14, 2021·Beilstein Journal of Organic Chemistry·Roslyn M RayKira Astakhova
Jun 17, 2021·Acta Biomaterialia·Minsong GaoJianzhao Liu

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Methods Mentioned

BETA
transfection
in vitro transcription
Assay
flow cytometry
ELISA
transfections
enzyme-linked immunosorbent assay

Software Mentioned

CellQuest
TriLink

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