Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
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DOI：
10.1039/d2cb00100d
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发表时间：
2022-06-08
影响因子：
4.1
通讯作者：
Brown, Tom
中科院分区：
文献类型：
--
作者：
Dysko, Anna;Baker, Ysobel R.;McClorey, Graham;Wood, Matthew J. A.;Fenner, Sabine;Williams, Glynn;El-Sagheer, Afaf;Brown, Tom
寡核苷酸正迅速成为治疗疑难杂症的有力药物。短单链寡核苷酸可以与靶RNA碱基对并改变基因表达，在遗传水平上提供了一种有吸引力的治疗方法。虽然在概念上很吸引人，但临床使用的寡核苷酸需要化学修饰。一种新出现的方法是用其他化学键如三唑代替磷酸二酯主链。三唑键固有地抵抗酶降解，提供体内稳定性，并且不带电，潜在地改善细胞渗透和体内分布。然而，已知三唑键会降低RNA靶结合亲和力。本研究表明，通过将芘或蒽醌连接到三唑5 '侧的核糖上，可以恢复双相稳定性并恢复含三唑寡核苷酸的剪接开关能力。寡核苷酸可以结合mRNA并改变基因表达，但临床使用时需要对主干进行修饰。我们表明，将芘或蒽醌连接到人工三唑主链旁边的核糖上，可以恢复细胞中的双相稳定性和剪接开关能力。
Oligonucleotides are rapidly emerging as powerful therapeutics for hard to treat diseases. Short single-stranded oligonucleotides can base pair with target RNA and alter gene expression, providing an attractive therapeutic approach at the genetic level. Whilst conceptually appealing, oligonucleotides require chemical modification for clinical use. One emerging approach is to substitute the phosphodiester backbone with other chemical linkages such as triazole. The triazole linkage is inherently resistant to enzymatic degradation, providing stability in vivo, and is uncharged, potentially improving cell-penetration and in vivo distribution. Triazole linkages, however, are known to reduce RNA target binding affinity. Here we show that by attaching pyrene or anthraquinone to the ribose sugar on the 5′-side of the triazole, it is possible to recover duplex stability and restore the splice switching ability of triazole-containing oligonucleotides. Oligonucleotides can bind to mRNA and alter gene expression, but require backbone modifications for clinical use. We show that attaching pyrene or anthraquinone to the ribose sugar next to an artificial triazole backbone restores duplex stability and splice switching ability in cells.
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DOI：
10.1039/c7cc05159j
发表时间：
2017-08-03
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Kumar P;El-Sagheer AH;Truong L;Brown T
通讯作者：
Brown T
影响因子：
4
作者：
Crooke ST
通讯作者：
Crooke ST
DOI：
10.1016/j.ymthe.2017.06.002
发表时间：
2017-09-06
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Liang XH;Sun H;Nichols JG;Crooke ST
通讯作者：
Crooke ST
影响因子：
1.8
作者：
BANNWARTH, W
通讯作者：
BANNWARTH, W
影响因子：
3.5
作者：
MORI, K;SUBASINGHE, C;COHEN, JS
通讯作者：
COHEN, JS