LAUSR

Aptameric receptors are important biosensor components, yet our ability to identify them depends on the target structures. We analyzed the contributions of individual functional groups on small molecules to binding within 27 target-aptamer pairs, identifying potential hindrances to receptor isolation—for example, negative cooperativity between sterically hindered functional groups. To increase the probability of aptamer isolation for important targets, such as leucine and voriconazole, for which multiple previous selection attempts failed, we designed tailored strategies focused on overcoming individual structural barriers to successful selections. This approach enables us to move beyond standardized protocols into functional group–guided searches, relying on sequences common to receptors for targets and their analogs to serve as anchors in regions of vast oligonucleotide spaces wherein useful reagents are likely to be found. Description Editor’s summary Developing highly selective aptamers, folded RNA or DNA oligonucleotides that bind to ligands, is a challenge because the sequence space is difficult to explore efficiently, nucleotides have limited chemical functionality, and methods for predicting RNA structure are not very accurate. Yang et al. developed an approach for sequential optimization of aptamers by modifying the target molecule with various functional groups. To design a sensor for the amino acid leucine, they used multiple derivatives to isolate aptamers with high affinity and selectivity. They then used a stepwise approach based on substructure to generate an aptamer for the antifungal drug voriconazole. —Michael A. Funk Concepts from organic and medicinal chemistry guide isolation of aptamers for small-molecule targets.