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Nucleic Acids Research Advance Access originally published online on January 16, 2009
Nucleic Acids Research 2009 37(4):1353-1362; doi:10.1093/nar/gkn1088
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Nucleic Acids Research, 2009, Vol. 37, No. 4 1353-1362
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry and Synthetic Biology

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

Mayumi Takahashi, Noriaki Minakawa* and Akira Matsuda*

Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan

*To whom correspondence should be addressed. Tel: +81 11 706 3228; Fax: +81 11 706 4980; Email: matuda{at}pharm.hokudai.ac.jp

Correspondence may also be addressed to Noriaki Minakawa. Tel: +81 11 706 3230; Fax: +81 11 706 4980; Email: noriaki@pharm.hokudai.ac.jp

Received December 17, 2008. Revised December 26, 2008. Accepted December 30, 2008.

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 (+16°C 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 3'-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.


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