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

Valentina M. Farzan, Egor A. Ulashchik, Yury V. Martynenko-Makaev, Maksim V. Kvach, Ilya O. Aparin, Vladimir A. Brylev, Tatiana A. Prikazchikova, Svetlana Yu Maklakova, Alexander G. Majouga, Alexey V. Ustinov, German A. Shipulin, Vadim V. Shmanai, Vladimir A. Korshun, Timofei S. Zatsepin

    Research output: Contribution to journalArticlepeer-review

    30 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)2599-2607
    Number of pages9
    JournalBioconjugate Chemistry
    Volume28
    Issue number10
    DOIs
    Publication statusPublished - 18 Oct 2017

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