Site-Selective Functionalization of Molecularly Imprinted Nanoparticles to Recognize Lysine-Rich Peptides

Sequence-selective binding of peptides has been a long-standing goal of chemists. As one of the most abundant amino acids in proteins, lysine plays an important role in protein functions as well as in antimicrobial and cell-penetrating peptides. Herein, we report molecularly imprinted nanoparticles (NPs) with high sequence selectivity for lysine-rich peptides. The NPs are prepared from molecular imprinting of cross-linkable surfactant micelles and postmodification of the imprinted pockets by photoaffinity labeling. The method allows carboxylic acids to be installed precisely near the lysine amino side chains, greatly enhancing the binding strengths of lysine-rich peptides. Small variations in the peptide sequence can be distinguished, and the binding affinity correlates positively with the number of lysine groups in model tripeptides. The method applies to complex lysine-rich biological peptides, achieving hundreds of nanomolar binding affinities and excellent binding specificities.