Sydnone-modified nucleosides as versatile tools for bioorthogonal post-synthetic functionalization of antisense oligonucleotides
Abstract
The development of efficient bioconjugation methods is essential for enhancing the therapeutic potential of oligonucleotides, especially antisense oligonucleotides (ASOs). Two main strategies are used for modification during oligonucleotide solid-phase synthesis: the early incorporation of functionalized monomers, or the post-synthetic modification of precursors bearing small reactive groups-the latter offering greater versatility and yield. Extensive efforts have been dedicated to incorporating bioorthogonal groups into phosphoramidite building blocks to enable the controlled chemical synthesis of reactive oligonucleotides suitable for post-synthetic modifications. Among these, alkynes and cyclooctynes are the most widely used, enabling Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) and strain-promoted azide-alkyne cycloaddition (SPAAC), respectively. We recently demonstrated the compatibility of the sydnone group with automated solid-phase chemistry. This chemical motif shows significant promise in oligonucleotide chemistry, as it allows for strain-promoted sydnone-alkyne cycloaddition (SPSAC), a reaction that has recently emerged as an efficient alternative to SPAAC for cellular studies. Herein, we present the synthesis of three sydnone-functionalized phosphoramidite monomers, their incorporation into ASOs, and an evaluation of their chemical and biological properties. These developments aim to expand the bioconjugation toolbox for ASO tracking, targeting, and imaging, thereby improving their therapeutic application and the understanding of intracellular mechanisms.
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BibTeX
@article{bristiel2026sydnonemodified,
title = {{Sydnone-modified nucleosides as versatile tools for bioorthogonal post-synthetic functionalization of antisense oligonucleotides}},
author = {Alexandra Bristiel and Alexandre Khuu and Mathilde Poulet and Frédéric Taran and Dominique Urban and Raphaël Guignard and Dominique Guianvarc’h},
journal = {RSC Chemical Biology},
year = {2026},
month = sep,
doi = {10.1039/d6cb00100a},
url = {https://hal.science/hal-05750094v1},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Sydnone-modified nucleosides as versatile tools for bioorthogonal post-synthetic functionalization of antisense oligonucleotides
AU - Alexandra Bristiel
AU - Alexandre Khuu
AU - Mathilde Poulet
AU - Frédéric Taran
AU - Dominique Urban
AU - Raphaël Guignard
AU - Dominique Guianvarc’h
PY - 2026
DA - 2026/09/15
JO - RSC Chemical Biology
DO - 10.1039/d6cb00100a
UR - https://hal.science/hal-05750094v1
AB - The development of efficient bioconjugation methods is essential for enhancing the therapeutic potential of oligonucleotides, especially antisense oligonucleotides (ASOs). Two main strategies are used for modification during oligonucleotide solid-phase synthesis: the early incorporation of functionalized monomers, or the post-synthetic modification of precursors bearing small reactive groups-the latter offering greater versatility and yield. Extensive efforts have been dedicated to incorporating bioorthogonal groups into phosphoramidite building blocks to enable the controlled chemical synthesis of reactive oligonucleotides suitable for post-synthetic modifications. Among these, alkynes and cyclooctynes are the most widely used, enabling Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) and strain-promoted azide-alkyne cycloaddition (SPAAC), respectively. We recently demonstrated the compatibility of the sydnone group with automated solid-phase chemistry. This chemical motif shows significant promise in oligonucleotide chemistry, as it allows for strain-promoted sydnone-alkyne cycloaddition (SPSAC), a reaction that has recently emerged as an efficient alternative to SPAAC for cellular studies. Herein, we present the synthesis of three sydnone-functionalized phosphoramidite monomers, their incorporation into ASOs, and an evaluation of their chemical and biological properties. These developments aim to expand the bioconjugation toolbox for ASO tracking, targeting, and imaging, thereby improving their therapeutic application and the understanding of intracellular mechanisms.
SN - 2633-0679
ER -