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 a-helical and b-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, 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.

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ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

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