Modulation of Src Kinase Activity by Selective Substrate Recognition with Pseudopeptidic Cages

The selective recognition of tyrosine residues in peptides is an appealing approach to inhibiting their tyrosine kinase (TK)-mediated phosphorylation. Herein, we describe pseudopeptidic cages that efficiently protect substrates from the action of the Src TK enzyme, precluding the corresponding Tyr phosphorylation. Fluorescence emission titrations show that the most efficient cage inhibitors strongly bind the peptide substrates with a very good correlation between the binding constant and the inhibitory potency. Structural insights and additional control experiments further support the proposed mechanism of selective supramolecular protection of the substrates. Moreover, the approach also works in a completely different kinase-substrate system. These results illustrate the potential of supramolecular complexes for the efficient and selective modulation of TK signaling.

Automated summary

The study introduces a new approach to selectively protect tyrosine residues in peptides from phosphorylation by the Src TK enzyme using pseudopeptidic cages. Fluorescence emission titrations indicate that the most efficient cage inhibitors strongly bind peptide substrates, with a good correlation between binding constant and inhibitory potency. Further experimental evidence supports the proposed mechanism of selectively protecting substrates through supramolecular interactions, showcasing the potential of supramolecular complexes for modulating TK signaling.