A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein–Protein Interaction Implicated in Breast Cancer

Abstract

Given the essential role of protein–protein interactions (PPIs) in cellular signaling pathways, their selective modulation is of great therapeutic interest. Mimicry of secondary structural protein elements has emerged as a promising strategy, with various scaffolds reproducing recognition surfaces of α–helical and β–strand/sheet proteins. A critical PPI, controlling cell growth and proliferation in breast and other cancers, occurs between growth factor receptor-bound protein 2 (Grb2) and a polyproline II (PPII) helix embedded in Gab2. Herein, the first example of a general approach for nonpeptidic mimicry of extended PPII helices is presented and it is demonstrated that the scaffold may be functionalized to recapitulate the binding characteristics of crucial hydrophobic and cationic Gab2 hot-spot side-chains. The rationally designed peptidomimetic binds Grb2 at the same position as Gab2 (protein-observed nuclear magnetic resonance (NMR)) with affinities comparable to the native peptide sequence (surface plasmon resonance (SPR)). With the addition of a new PPII minimalist scaffold, these studies further validate the use of diverse secondary structure peptidomimetics in disrupting therapeutically relevant PPIs.