Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain.
Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER BBN), Jordi Girona 18-26, E-08034 Barcelona, Spain.
Int J Mol Sci. 2020 Dec 24;22(1):121. doi: 10.3390/ijms22010121.
Two G-quadruplex forming oligonucleotides [d(TGT) and d(TGT)] were selected as two tetramolecular quadruplex nanostructures because of their demonstrated ability to be modified with hydrophobic molecules. This allowed us to synthesize two series of G-quadruplex conjugates that differed in the number of G-tetrads, as well as in the terminal position of the lipid modification. Both solution and solid-phase syntheses were carried out to yield the corresponding lipid oligonucleotide conjugates modified at their 3'- and 5'-termini, respectively. Biophysical studies confirmed that the presence of saturated alkyl chains with different lengths did not affect the G-quadruplex integrity, but increased the stability. Next, the G-quadruplex domain was added to an 18-mer antisense oligonucleotide. Gene silencing studies confirmed the ability of such G-rich oligonucleotides to facilitate the inhibition of target luciferase without showing signs of toxicity in tumor cell lines.
选择了两个 G-四链体形成寡核苷酸 [d(TGT) 和 d(TGT)]，因为它们具有被疏水分子修饰的能力，被证明能够形成四分子的 G-四链体纳米结构。这使得我们能够合成两种 G-四链体缀合物系列，它们在 G-四联体的数量以及脂质修饰的末端位置上有所不同。分别通过溶液相和固相合成得到了在 3'-和 5'-末端修饰的相应脂质寡核苷酸缀合物。生物物理研究证实，不同长度的饱和烷基链的存在不会影响 G-四链体的完整性，反而会增加其稳定性。接下来，将 G-四链体结构域添加到 18 个碱基对的反义寡核苷酸中。基因沉默研究证实，这种富含 G 的寡核苷酸能够促进靶标荧光素酶的抑制，而在肿瘤细胞系中没有表现出毒性的迹象。
