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Probing three-dimensional cyclooctatetraene for nucleobase modification in aptamer selection.
Greta Charlotte Dahm1, Usman Akhtar1,2, Alix Bouvier-Müller1
1Institut Pasteur, Université Paris Cité, CNRS UMR3523, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, Paris Cedex 15, France.
Communications Chemistry
|September 15, 2025
Summary
Researchers developed novel aptamers using cyclooctatetraene carboxylate (COTc) modification. These aptamers show enhanced binding affinity for the PvLDH biomarker, offering a promising alternative to traditional aromatic compounds in drug discovery.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Aptamer modifications enhance binding properties by enabling alternative binding modes.
- Current modifications often mimic amino acid side chains or use sp2-hybridized moieties.
- Drug discovery trends favor sp3-rich compounds over aromatic derivatives.
Purpose of the Study:
- To explore the utility of cyclooctatetraene carboxylate (COTc) modified nucleotides in aptamer development.
- To identify high-affinity aptamers against the Plasmodium falciparum lactate dehydrogenase (PvLDH) biomarker.
- To assess COTc as a bioisostere for aromatic moieties in functional nucleic acids.
Main Methods:
- Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was employed.
- Nucleotides were modified with cyclooctatetraene carboxylate (COTc).
- Binding affinities of generated aptamers were determined by measuring dissociation constants.
Main Results:
- Novel aptamers targeting PvLDH were successfully identified.
- These aptamers exhibited dissociation constants in the low nanomolar (nM) range.
- Performance surpassed previously identified cubamers.
Conclusions:
- Cyclooctatetraene carboxylate (COTc) is effective for aptamer modification.
- COTc-modified aptamers demonstrate improved binding affinity for PvLDH.
- COTc serves as a valuable bioisostere for aromatic groups in aptamers and small molecules.
