Target-switch SELEX: Screening with alternating targets to generate aptamers to conserved terminal dipeptides

Systematic evolution of ligands by exponential enrichment (SELEX) encompasses a wide variety of high-throughput screening techniques for producing nucleic acid binders to molecular targets through directed evolution. We describe here the design and selection steps for discovery of DNA aptamers with specificity for the two consecutive N-terminal amino acids (AAs) of a small peptide (8–10 amino acids). This bead-based method may be adapted for applications requiring binders which recognize a specific portion of the desired target. For complete details on the use and execution of this protocol, please refer to Hong et al. (2022).