A Cyclized Helix-Loop-Helix Peptide as a Molecular Scaffold for Cell-Membrane Permeable Inhibitors for the Interaction Between Estrogen Receptor α and Coactivator SRC1.

The molecular design of inhibitors against intracellular protein-protein interactions (PPIs) is of interest for drug discovery and chemical biology. Herein, a novel cyclized helix-loop-helix (cHLH) peptide that inhibited the intracellular PPI between estrogen receptor alpha (ERα) and coactivator SRC1 are designed. The peptide, cHLH-ERα, bound to ERα and inhibited the interaction between ERα and the coactivator SRC1. Cellular imaging and yeast reporter assays showed that cHLH-ERα penetrated the cell membrane and exhibited antagonistic activity against ERα-SRC1 to inhibit the growth of a breast cancer cell.