Peptide Inhibitors of Protein-Protein Interactions Targeted to Src Homology 2 Domains: A Combined Computational and Spectroscopic Design Approach

SHP2 is an important molecular target for therapies against cancer and rare diseases, like RASopathies [1,2].Mutations of the gene coding for SHP2, PTPN11, have been associated with cancer and developmental disorders.The structure of SHP2 includes two SH2 domains (N-SH2 and C-SH2) followed by the catalytic domain PTP.SH2 domains recognize and bind phosphopeptide [3].They also have an important role in modulating the catalytic activity of the protein.Under basal conditions, the N-SH2 domain blocks the catalytic site and SHP2 is inactive.The association to binding partners favors a conformational transition from this autoinhibited conformation to an active state.Most of the SHP2 pathological amino acid substitutions perturb the autoinhibitory interaction in favor of open conformations, resulting in a hyperactivated protein [4].SHP2 can be efficiently inhibited by targeting the binding of the N-SH2 domain to cognate proteins [5], furthermore the development of inhibitors of SHP2 protein-protein interactions can take advantage of the role of the C-SH2 domain for increasing both specificity and affinity.Check P2.128 !!! C. Innamorati In vivo activity N-terminal and C-term portions of phosphopeptides can form different ionpair interactions with the residue of the C-SH2 domain.