Synthesis and characterization of 2'-modified-4'-thioRNA: a comprehensive comparison of nuclease stability

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概要

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• We report herein the synthesis and physical and physiological characterization of fully modified 2’-modified-4’-thioRNAs, i.e. 2’-fluoro-4’-thioRNA (F-SRNA) and 2’-O-Me-4’-thioRNA (Me-SRNA), which can be considered as a hybrid chemical modification based on 2’-modified oligonucleotides (ONs) and 4’-thioRNA (SRNA). In its hybridization with a complementary RNA, F-SRNA (15mer) showed the highest Tm value (+168C relative to the natural RNA duplex). In addition, both F-SRNA and Me-SRNA preferred RNA as a complementary partner rather than DNA in duplex formation. The results of a comprehensive comparison of nuclease stability of single-stranded F-SRNA and Me-SRNA along with 2’-fluoroRNA (FRNA), 2’-O-MeRNA (MeRNA), SRNA, and natural RNA and DNA, revealed that Me-SRNA had the highest stability with t1/2 values of>24 h against S1 nuclease (an endonuclease) and 79.2 min against SVPD (a ’-exonuclease). Moreover, the stability of Me-SRNA was significantly improved in 50% human plasma (t1/2 = 1631 min) compared with FRNA (t1/2 = 53.2 min) and MeRNA (t1/2 = 187 min), whose modifications are currently used as components of therapeutic aptamers. The results presented in this article will, it is hoped, contribute to the development of 2’-modified- 4’-thioRNAs, especially Me-SRNA, as a new RNA molecule for therapeutic applications.

• Oxford University Pressの論文

著者

• Matsuda Akira

  北海道大学 薬研究

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