# 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

## TL;DR

Scientists designed a cell-permeable peptide that inhibits a key interaction in breast cancer cells, potentially leading to new treatment strategies.

## Contribution

A novel cyclized helix-loop-helix peptide scaffold was developed to inhibit estrogen receptor alpha and coactivator SRC1 interactions.

## Key findings

- The cHLH-ERα peptide successfully inhibited the ERα-SRC1 interaction in cells.
- The peptide demonstrated cell membrane permeability and antagonistic activity against breast cancer cell growth.

## Abstract

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.

A cyclized helix‐loop‐helix (cHLH) peptide is used as a molecular scaffold to generate cell‐permeable protein–protein interactions inhibitors by bifunctional grafting. The steroid receptor coactivator‐1 (SRC1) epitope (red) was grafted onto the C‐terminal helix, and six arginine residues (cyan) were grafted onto the other helix. The designed peptide cHLH‐ERα inhibited the estrogen receptor α (ERα)–SRC1 interaction and showed cell membrane permeability.© 2025 WILEY‐VCH GmbH