ヌクレアーゼ抵抗性化学修饰核酸の开发研究 development - j-stage.pdf

YAKUGAKU ZASSHI 131(2) 285―298 (2011) 2011 The Pharmaceutical Society of Japan 285285 ―Review― ヌクレアーゼ抵抗性化学修飾核酸の開発研究 松田　彰 Development of Highly Nuclease-resistant Chemically-modiˆed Oligonucleotides Akira MATSUDA Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060 0812, Japan ( ) Received June 28, 2010 ( ) Chemical modiˆcation of therapeutic oligodeoxyribonucleotides ODNs is necessary to avoid not only degrada- tion by endo- and exo-nucleases but also recognition by sensors such as an innate immune system. We have been de- veloping modiˆed nucleosides having an aminoalky linker at the pyrimidine nucleobase or sugar moiety. ODNs contain- ing 5- ( ) ′ ( ) ° N- 6-aminohexyl carbamoyl-2 -deoxyuridine 7 were thermally stabilized about 3 C per modiˆcation and were about 160 times more stable to hydrolysis by snake venom phosphodiesterase ( ′ ) a 3 -exonuclease than unmodiˆed ODNs, but not by endonucleases. On the other hand, ODNs containing 4′ ( ) ( ) -C- aminoethyl thymidine 14b , which was synthesized by a newly developed radical cyclization-