Link to DOI – 10.1038/s42004-025-01629-5
Commun. Chem. 2025, 8, 276
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 2
-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.