Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties

S. K. Miroshnichenko, O. A. Patutina, E. A. Burakova, B. P. Chelobanov, A. A. Fokina, V. V. Vlassov, Sidney Altman, M. A. Zenkova, D. A. Stetsenko

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Here we describe a DNA analog in which the mesyl (methanesulfonyl) phosphoramidate group is substituted for the natural phosphodiester group at each internucleotidic position. The oligomers show significant advantages over the often-used DNA phosphorothioates in RNA-binding affinity, nuclease stability, and specificity of their antisense action, which involves activation of cellular RNase H enzyme for hybridization-directed RNA cleavage. Biological activity of the oligonucleotide analog was demonstrated with respect to pro-oncogenic miR-21. A 22-nt anti–miR-21 mesyl phosphoramidate oligodeoxynucleotide specifically decreased the miR-21 level in melanoma B16 cells, induced apoptosis, reduced proliferation, and impeded migration of tumor cells, showing superiority over isosequential phosphorothioate oligodeoxynucleotide in the specificity of its biological effect. Lower overall toxicity compared with phosphorothioate and more efficient activation of RNase H are the key advantages of mesyl phosphoramidate oligonucleotides, which may represent a promising group of antisense therapeutic agents.

Original languageEnglish (US)
Pages (from-to)1229-1234
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number4
DOIs
StatePublished - Jan 22 2019

Keywords

  • MiR-21
  • Oncogenic microRNA
  • Phosphorothioate DNA

ASJC Scopus subject areas

  • General

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