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 signalling 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 Grb2 and a polyproline II (PPII) helix embedded in Gab2. Herein, we present the first example of a general approach for non-peptidic mimicry of extended PPII helices and demonstrate that the scaffold may be functionalised 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 NMR) with affinities comparable to the native peptide sequence (SPR). With the addition of a new polyproline II minimalist scaffold these studies further validate the use of diverse secondary structure peptidomimetics in disrupting therapeutically relevant PPIs.