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

    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

    Fingerprint

    Antisense Oligonucleotides
    Ribonuclease H
    Oligodeoxyribonucleotides
    Oligonucleotides
    RNA Cleavage
    Experimental Melanomas
    DNA
    Cell Movement
    RNA
    Apoptosis
    Enzymes
    phosphoramidic acid
    Neoplasms
    Therapeutics

    Keywords

    • MiR-21
    • Oncogenic microRNA
    • Phosphorothioate DNA

    ASJC Scopus subject areas

    • General

    Cite this

    Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties. / Miroshnichenko, S. K.; Patutina, O. A.; Burakova, E. A.; Chelobanov, B. P.; Fokina, A. A.; Vlassov, V. V.; Altman, Sidney; Zenkova, M. A.; Stetsenko, D. A.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 4, 22.01.2019, p. 1229-1234.

    Research output: Contribution to journalArticle

    Miroshnichenko, S. K. ; Patutina, O. A. ; Burakova, E. A. ; Chelobanov, B. P. ; Fokina, A. A. ; Vlassov, V. V. ; Altman, Sidney ; Zenkova, M. A. ; Stetsenko, D. A. / Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 4. pp. 1229-1234.
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    AU - Chelobanov, B. P.

    AU - Fokina, A. A.

    AU - Vlassov, V. V.

    AU - Altman, Sidney

    AU - Zenkova, M. A.

    AU - Stetsenko, D. A.

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