Quantitative Heterodimerization of Aromatic Peptides through Host-Enhanced Polar–π Interactions for On-Resin Recognition

Peptide dimerization plays an important role in both natural and artificial supramolecular systems. A major challenge to date is the quantitative heterodimerization of two peptides without formation of homodimers. Here, we employ a macrocyclic host to simultaneously encapsulate a canonical aromatic peptide and a non-canonical perfluorophenylalanine-containing peptide through polar–π interactions, thus forming an unprecedented new series of heteropeptide dimers with high binding affinity. This new peptide heterodimerization was applied to on-resin recognition and separation of aromatic peptides in a peptide mixture exhibiting over 95% isolation purity. This research unveils a generic approach to exploit quantitative heteropeptide dimers for the design of supramolecular (bio)systems.