Link to Pubmed [PMID] – 40954195
Link to DOI – 10.1038/s42004-025-01629-5
Commun Chem 2025 Sep; 8(1): 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 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.