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<p>Decoration of aptamers with chemical modifications at the level of nucleobases grants access to alternative binding modes, which often result in improved binding properties. Most functional groups involved in such endeavours mimic the side chains of amino acids or are based on sp<sup>2</sup>-dominated moieties. While this approach has met undeniable success, trends in modern drug discovery seem to favor sp<sup>3</sup>-rich compounds over aromatic derivatives. Here, we report the use of a nucleotide modified with the three-dimensional, highly flexible cyclooctatetraene carboxylate (COTc). This nucleotide was engaged in an SELEX experiment against the biomarker PvLDH. Tightly binding aptamers were identified, which displayed dissociation constants in the low nM range, representing a significant improvement compared to previously identified cubamers. These modified aptamers clearly underscore the usefulness of COTc as a bioisostere replacement of aromatic moieties not only in small compounds but also in functional nucleic acids.</p>

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Probing three-dimensional cyclooctatetraene for nucleobase modification in aptamer selection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月15日

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  • Greta Charlotte Dahm,
  • Usman Akhtar,
  • Alix Bouvier-Müller,
  • Laura Lim,
  • Fabienne Levi-Acobas,
  • Pierre Nicolas Bizat,
  • Germain Niogret,
  • Julian A. Tanner,
  • Frédéric Ducongé,
  • Marcel Hollenstein

摘要

Decoration of aptamers with chemical modifications at the level of nucleobases grants access to alternative binding modes, which often result in improved binding properties. Most functional groups involved in such endeavours mimic the side chains of amino acids or are based on sp2-dominated moieties. While this approach has met undeniable success, trends in modern drug discovery seem to favor sp3-rich compounds over aromatic derivatives. Here, we report the use of a nucleotide modified with the three-dimensional, highly flexible cyclooctatetraene carboxylate (COTc). This nucleotide was engaged in an SELEX experiment against the biomarker PvLDH. Tightly binding aptamers were identified, which displayed dissociation constants in the low nM range, representing a significant improvement compared to previously identified cubamers. These modified aptamers clearly underscore the usefulness of COTc as a bioisostere replacement of aromatic moieties not only in small compounds but also in functional nucleic acids.