Alnylam Pharmaceuticals, 675 West Kendall Street, Cambridge, MA 02142, USA.
Axolabs GmbH, Fritz-Hornschuch-Strasse 9, 95326 Kulmbach, Germany.
Chem Commun (Camb). 2024 Nov 5;60(89):13024-13027. doi: 10.1039/d4cc04302b.
Conformationally constrained nucleotides, LNA or α-L-LNA, at the 5' terminus of the antisense strand impeded gene silencing of small interfering RNA (siRNA) by hindering phosphorylation, thereby deterring loading into the RNA-induced silencing complex. Installation of a phosphate mimic, ()-vinyl phosphonate (VP), improved activity considerably. Gene silencing was more efficient when the antisense strand of the siRNA was modified with 5'-VP-α-L-LNA, which adopts a C3'- (south) conformation, than when the antisense strand was modified with 5'-VP-LNA, which adopts a C3'- (north) pucker. These data underscore the critical role of conformation of nucleotides in RNA interference.
5' 末端的反义链上的构象受限核苷酸、LNA 或 α-L-LNA 会通过阻碍磷酸化来阻碍小干扰 RNA (siRNA) 的基因沉默，从而阻止其装入 RNA 诱导的沉默复合物。安装磷酸类似物 ()-乙烯基膦酸 (VP) 可大大提高其活性。当 siRNA 的反义链用 5'-VP-α-L-LNA 修饰时，其采用 C3'-(南)构象，比用 5'-VP-LNA 修饰时的基因沉默效率更高，后者采用 C3'-(北)构象。这些数据强调了核苷酸构象在 RNA 干扰中的关键作用。
