Probing three-dimensional cyclooctatetraene for nucleobase modification in aptamer selection
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.
Authors
- Germain Niogret (ORCID: https://orcid.org/0009-0002-6185-0183)
- Frederic Ducongè (ORCID: https://orcid.org/0000-0002-8595-0050)
- Julian A. Tanner (ORCID: https://orcid.org/0000-0002-5459-1526)
- Fabienne Lévi-Acobas (ORCID: https://orcid.org/0000-0001-5022-2873)
- G. Dahm
- Marcel Hollenstein (ORCID: https://orcid.org/0000-0003-0263-9206)
- Usman Akhtar (ORCID: https://orcid.org/0000-0002-7124-0656)
- Alix Bouvier‐Müller (ORCID: https://orcid.org/0000-0002-6399-2102)
- Laura Lim
- Pierre Nicolas Bizat (ORCID: https://orcid.org/0009-0004-1583-6238)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Forman Christian College (PK)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR)
- Direction de la Recherche Fondamentale (FR)
- CEA Paris-Saclay (FR)
- Nano and Advanced Materials Institute (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2025-09-15
- DOI
- https://doi.org/10.1038/s42004-025-01629-5
- Citations
- 2
- Primary Topic
- Advanced biosensing and bioanalysis techniques
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique