Src homology 2 domain proteomimetics: developing phosphopeptide selective receptors

SH2 domains are the paradigm of phosphotyrosine protein recognition modules and are involved in mediating numerous cancer-promoting protein–protein complexes. In an effort to develop protein-selective receptors for inhibition of protein complexation events, we herein report the de novo rational and computationally aided design of SH2 domain proteomimetics. Lead mimetics exhibit target phosphopeptide selectivity (Ka ≈ 107 M−1) and potently disrupt SH2 domain:phosphopeptide interactions.