Automated Solid-Phase Click Synthesis of Oligonucleotide Conjugates: From Small Molecules to Diverse N-Acetylgalactosamine Clusters,Bioconjugate Chemistry

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Automated Solid-Phase Click Synthesis of Oligonucleotide Conjugates: From Small Molecules to Diverse N-Acetylgalactosamine Clusters
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-10-04 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00462
Valentina M. Farzan ₁ , Egor A. Ulashchik ₂ , Yury V. Martynenko-Makaev ₂ , Maksim V. Kvach ₂ , Ilya O. Aparin ₃ , Vladimir A. Brylev ₃ , Tatiana A. Prikazchikova ₁ , Svetlana Yu. Maklakova ₄ , Alexander G. Majouga _{4,

5} , Alexey V. Ustinov ₃ , German A. Shipulin ₆ , Vadim V. Shmanai ₂ , Vladimir A. Korshun _{3,

7} , Timofei S. Zatsepin _{1,

4,

6}

Affiliation

We developed a novel technique for the efficient conjugation of oligonucleotides with various alkyl azides such as fluorescent dyes, biotin, cholesterol, N-acetylgalactosamine (GalNAc), etc. using copper-catalysed alkyne–azide cycloaddition on the solid phase and CuI·P(OEt)₃ as a catalyst. Conjugation is carried out in an oligonucleotide synthesizer in fully automated mode and is coupled to oligonucleotide synthesis and on-column deprotection. We also suggest a set of reagents for the construction of diverse conjugates. The sequential double-click procedure using a pentaerythritol-derived tetraazide followed by the addition of a GalNAc or Tris–GalNAc alkyne gives oligonucleotide–GalNAc dendrimer conjugates in good yields with minimal excess of sophisticated alkyne reagents. The approach is suitable for high-throughput synthesis of oligonucleotide conjugates ranging from fluorescent DNA probes to various multi-GalNAc derivatives of 2′-modified siRNA.

中文翻译：

寡核苷酸缀合物的自动固相点击合成：从小分子到不同的N-乙酰半乳糖胺簇

我们开发了一种新技术，可通过在固相上使用铜催化的炔-叠氮化物环加成反应，将寡核苷酸与各种烷基叠氮化物（例如荧光染料，生物素，胆固醇，N-乙酰半乳糖胺（GalNAc）等）进行有效偶联，该方法是在铜上催化铜-炔-叠氮化物环加成的。 OEt）₃作为催化剂。在寡核苷酸合成仪中以全自动模式进行缀合，并偶联至寡核苷酸合成和柱上脱保护。我们还建议了一套用于构建多种缀合物的试剂。使用季戊四醇衍生的四叠氮化物的顺序双击程序，然后添加GalNAc或Tris-GalNAc炔烃，可以以极高的收率获得寡核苷酸-GalNAc树枝状大分子共轭物，而所需的复杂炔烃试剂却极少。该方法适用于寡核苷酸偶联物的高通量合成，寡核苷酸偶联物的范围从荧光DNA探针到2'-修饰的siRNA的各种multi-GalNAc衍生物。

更新日期：2017-10-04

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