Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.
UMR Genetique Moleculaire, Genomique, Microbiologie (GMGM), Strasbourg University-CNRS, 67084 Strasbourg, France.
Molecules. 2021 Apr 7;26(8):2119. doi: 10.3390/molecules26082119.
One of the ways to efficiently deliver various drugs, including therapeutic nucleic acids, into the cells is conjugating them with different transport ligands via labile or stable bonds. A convenient solid-phase approach for the synthesis of 5'-conjugates of oligonucleotides with biodegradable pH-sensitive hydrazone covalent bonds is proposed in this article. The approach relies on introducing a hydrazide of the ligand under aqueous/organic media to a fully protected support-bound oligonucleotide containing aldehyde function at the 5'-end. We demonstrated the proof-of-principle of this approach by synthesizing 5'-lipophilic (e.g., cholesterol and α-tocopherol) conjugates of modified siRNA and non-coding RNAs imported into mitochondria (antireplicative RNAs and guide RNAs for Mito-CRISPR/system). The developed method has the potential to be extended for the synthesis of pH-sensitive conjugates of oligonucleotides of different types (ribo-, deoxyribo-, 2'--methylribo-, and others) with ligands of different nature.
将各种药物（包括治疗性核酸）高效递送到细胞内的方法之一是通过不稳定或稳定的键将它们与不同的转运配体缀合。本文提出了一种在水/有机介质中向完全保护的固载寡核苷酸中引入配体的酰腙共价键的 5'-缀合的方便的固相方法，该寡核苷酸在 5'-端含有醛基。我们通过合成亲脂性 5'（例如胆固醇和α-生育酚）修饰的 siRNA 和导入线粒体的非编码 RNA（抗复制 RNA 和 Mito-CRISPR/system 的向导 RNA）的共轭物，证明了该方法的原理。所开发的方法有可能扩展到合成具有不同性质的配体的不同类型（核糖、脱氧核糖、2'-甲基核糖等）的寡核苷酸的 pH 敏感共轭物。
