SHP-2 peptide inhibitors: studies on the mechanism of protein activation.

The protein tyrosin-phosphatase SHP-2 works as a positive modulator that participates in the overregulation of signal transduction pathways and causes various diseases such as cancer, childhood leukemias, and Noonan syndrome. Its inhibitors could be peptides, which bind the N-SH2 or C-SH2 domains of SHP-2, to keep the protein in a nonactive conformation. In this work, we first focused on optimising peptide sequences that interact with the N-SH2 domain, synthesising a sequence characterised by a large steric hindrance. Then, we focused on studying the mechanism of the protein activation. We synthesised some sequences that are already known from the literature that are able to inactivate the protein; then, the same sequences were synthesised using a non-natural analogue of phosphotyrosine to avoid dephosphorylation. The key point is how this sequence inhibits the conformational change: does activation occur simultaneously with the binding or only after the approach?