Drug Discov Ther. 2016;10(5):263-270. (DOI: 10.5582/ddt.2016.01055)

In vitro and in vivo biophysical properties of oligonucleotides containing 5'-thio nucleosides.

Islam MA, Waki R, Fujisaka A, Ito KR, Obika S


Phosphorothioate modification is one of the most widely investigated and promising chemical modifications in oligonucleotide (ON) based therapeutics. Structurally similar 5'-thio or phosphorothiolate-modified nucleotides, in which a 5'-bridging oxygen is replaced with a sulfur atom, are gaining importance for ON-based research. Several reports have been published describing the synthesis of 5'-thio-modified ONs but no detailed in vitro and in vivo data are available. Here, we report the synthesis of 5'-thio-modified 2'-deoxy-5-methylcytidine. 5'-Thio-modified thymidine and 2'-deoxy-5-methylcytidine were incorporated into target ONs, then we evaluated their binding affinity, nuclease stability, RNase H mediated scission, stability in blood serum, and in vitro and in vivo activity. This is the first report showing the influence of 5'-thio-modified antisense ONs in in vitro and in vivo experiments.

KEYWORDS: Phosphorothiolate, methylcytosine, RNase H activity, in vitro and in vivo antisense activity

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