James Luccarelli, Philip C Simister, Andrew D Hamilton, Stephan M Feller, Sam Thompson
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引用次数: 0
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.
期刊介绍:
ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).