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

• Published in: Drug Discoveries & Therapeutics Vol. 10; no. 5; pp. 263 - 270
• Main Authors: Islam, Md Ariful, Waki, Reiko, Fujisaka, Aki, Ito, Kosuke Ramon, Obika, Satoshi
• Format: Journal Article
• Language: English
• Published: Japan International Research and Cooperation Association for Bio & Socio-Sciences Advancement 01.01.2016
• Subjects: Animals; Drug Stability; in vitro and in vivo antisense activity; Male; methylcytosine; Mice; Mice, Inbred C57BL; Oligonucleotides - chemistry; Phosphorothiolate; Ribonuclease H - metabolism; RNase H activity; Thionucleosides - chemistry
• ISSN: 1881-7831; 1881-784X
• DOI: 10.5582/ddt.2016.01055

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.