Kikuta Kenji, Taniguchi Yosuke, Sasaki Shigeki
Graduate School of Pharmaceutical Sciences, Kyushu University.
Chem Pharm Bull (Tokyo). 2019;67(8):877-883. doi: 10.1248/cpb.c19-00337.
The 4-vinylpyrimidin-2-one nucleoside (T-vinyl) forms a cross-link with the RNA containing uracil at the complementary site at a high reaction rate. To obtain the stable T-vinyl derivative so that its reactivity is protected until it access to the target site, several derivatives were investigated, and the 2-thiopyridinyl- and 2-thiopyrimidinyl T-vinyl derivatives were determined to be good candidates. The 2-thiopyrimidinyl T-vinyl derivative was found to more efficiently cross-link with mRNA albeit having a better stability than the 2-thiopyridinyl T-vinyl derivative. The investigation using the luciferase (Luc) mRNA, the synthetic mRNA and non-cellular translation system revealed that the translation is terminated at the end of the cross-linked duplex between the mRNA and the oligoribonucleotide (ORN). Thus, the 2-thiopyrimidinyl T-vinyl derivative has successfully demonstrated both a good stability and high efficiency for the cross-linking reaction, and expanded its applicability in biological applications.
4-乙烯基嘧啶-2-酮核苷（T-乙烯基）能与在互补位点含有尿嘧啶的RNA以高反应速率形成交联。为了获得稳定的T-乙烯基衍生物，使其反应活性在到达靶位点之前得到保护，研究了几种衍生物，结果确定2-硫代吡啶基和2-硫代嘧啶基T-乙烯基衍生物是很好的候选物。发现2-硫代嘧啶基T-乙烯基衍生物尽管比2-硫代吡啶基T-乙烯基衍生物具有更好的稳定性，但能更有效地与mRNA交联。使用荧光素酶（Luc）mRNA、合成mRNA和无细胞翻译系统进行的研究表明，翻译在mRNA与寡核糖核苷酸（ORN）之间的交联双链体末端终止。因此，2-硫代嘧啶基T-乙烯基衍生物成功地展示了良好的稳定性和交联反应的高效率，并扩大了其在生物应用中的适用性。
