Accomplishing a feat that has “eluded supramolecular chemists for decades,” researchers say they have discovered the first synthetic receptor that binds a peptide sequence in aqueous solution with nanomolar affinity and high specificity, like antibodies do. The receptor-peptide pairing could be useful as an affinity tag for various biological applications. Synthetic receptors are smaller, more stable, more recyclable, and much less expensive than antibodies. But they generally bind peptides with millimolar to micromolar affinities—orders of magnitude less avidly than antibodies. Adam R. Urbach and coworkers at Trinity University, in San Antonio, discovered that the tripeptide Tyr-Leu-Ala binds the donut-shaped synthetic receptor cucurbituril (Q8) with 7.2-nM affinity (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b00718). The strength of the interaction decreases by three orders of magnitude if Leu and Ala trade places in the tripeptide, exemplifying the receptor’s high specificity. The researchers found the interaction by using a fluorescent indicator to search a broad range of peptide sequences for Q8 binding. Modeling predicts that Tyr and Leu bind snugly inside Q8’s ring and that five hydrogen bonds stabilize the interaction, helping account for its strength.