Modulation of Src kinase activity by selective substrate recognition with pseudopeptidic cages.

The selective recognition of tyrosine (Tyr) residues in peptides is an appealing approach to inhibit their phosphorylation mediated by tyrosine kinases (TKs). Here we describe pseudopeptidic cages that efficiently protect the substrates from the action of the Src TK enzyme, precluding the corresponding Tyr phosphorylation. The most efficient cage inhibitors strongly bind the peptide substrates as shown by fluorescence emission titrations, with a very good correlation between the binding constants and the inhibitory potency. Structural insights and additional control experiments further support the proposed mechanism by the 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.