De novo grafted coiled-coil peptides as p53/hDM2 inhibitors

Abstract

Dysregulation of protein–protein interactions (PPIs) plays a key role in disease progression. PPI interfaces have long been considered challenging targets to drug due to their large surface areas and lack of well-defined binding sites suitable for small molecules. Peptide-based ligands offer the opportunity to mimic the action of a native binding partner to inhibit PPIs. Previously, we have used the extensively characterized de novo, parallel, homodimeric coiled coil, CC-Di, as a template to design selective inhibitors of the NOXA-B/MCL-1 PPI. To further establish that coiled coils offer the possibility of modulating α helix-mediated PPIs, we show that this approach can be adapted to design coiled coils that are competitive inhibitors of the p53/hDM2 PPI with sub-micromolar (μM) affinities, as demonstrated by fluorescence anisotropy.