Probing three-dimensional cyclooctatetraene as 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 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 (COT). This nucleotide was engaged in a SELEX experiment against the biomarker PvLDH. Tightly binding aptamers, coined COTmers, were identified which displayed dissociation constants in the low nM range, representing a significant improvement compared to previously identified cubamers. COTmers clearly underscore the usefulness of COT as a bioisostere replacement of aromatic moieties not only in small compounds but also in functional nucleic acids.