Department of Chemical Sciences, Università degli Studi di Napoli Federico II, via Cintia, 80126, Napoli, Italy.
Rega Institute for Medical Research, Herestraat 49-box 1041, 3000, Leuven, Belgium.
Chemistry. 2020 Aug 3;26(43):9589-9597. doi: 10.1002/chem.202001504. Epub 2020 Jul 9.
The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172-T 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.
已设计用基于己糖醇的核苷酸替换强效 α-凝血酶结合适体 NU172 中的一个或多个核苷酸残基，以研究这些取代对抗凝剂理化和功能特性的影响。在 NU172 的 T9 和 G18 位置掺入单个己糖醇核苷酸，由于己糖醇主链的仿生特性，实质上保留了亲本寡核苷酸的理化特征。重要的是，NU172-T9 突变体对人 α-凝血酶的结合亲和力高于天然适体，并且即使在 90%人血清中 24 小时后稳定性也得到改善，半衰期估计值显著增加。修饰的寡核苷酸的抗凝活性也被发现略优于 NU172。总体而言，这些结果证实了己糖醇核苷酸作为仿生试剂的潜力，同时为开发受 NU172 启发的 α-凝血酶结合适体奠定了基础。
