Development of activity-based probes with tunable specificity for protein tyrosine phosphatase subfamilies

Herein we describe the development of activity-based probes toward protein tyrosine phosphatase (PTP) subfamilies. A novel phosphotyrosine analog serving as the latent trapping unit has been designed and explored. It allows addition of various amino acid residues to its C- and N-termini to extend the recognition element. As a proof-of-concept, we have synthesized three tripeptide probes, which carry the phosphotyrosine analog in the middle position and a leucinamide residue at the C-terminus. The three tripeptide probes differed only in their N-terminal amino acid (Glu, Phe, and Lys). The labeling properties of these probes were determined and the results showed the newly synthesized probes could selectively label PTPs in an activity-dependent manner. In addition, the probes’ target specificity was also shown to be influenced by the amino acid residues flanking the phosphotyrosine analog.