2026-06-03 スイス連邦工科大学ローザンヌ校（EPFL）
Membrane-permeable cyclic peptide that inhibits the intracellular Keap1-Nrf2 protein-protein interaction. Credit: Christian Heinis ©2026 EPFL
＜関連情報＞
- https://actu.epfl.ch/news/new-peptides-slip-into-cells-to-block-hard-to-targ/
- https://www.nature.com/articles/s41589-026-02237-7
タンパク質間相互作用を阻害する膜透過性環状ペプチドの生成 Generation of membrane-permeable cyclic peptides inhibiting protein–protein interaction
Xinjian Ji,Lluc Farrera-Soler,Jiajun Li,Gontran Sangouard,Nathan De Sadeleer,Alexander L. Nielsen,Ganesh K. Mothukuri,Anne Zarda,Edward J. Will,Florence Pojer,Kelvin Lau & Christian Heinis
Nature Chemical Biology Published:01 June 2026
DOI:https://doi.org/10.1038/s41589-026-02237-7
Abstract
Small, nonpolar cyclic peptides can both bind challenging targets and cross cell membranes, making them attractive for addressing currently undruggable targets such as many protein–protein interactions (PPIs). However, developing such compounds de novo without prior information about lead structures such as natural ligands or fragments remains a notable challenge. Here we show that functional screening of structurally highly diverse cyclic peptide libraries synthesized at nanomole scale allows identification of sub-kDa inhibitors of a PPI. By screening 15,360 fully random cyclic peptides, we were able to identify an inhibitor of the E3 ligase adaptor Keap1 and its substrate Nrf2. Optimization by rapid design–build–test cycles produced a membrane-permeable compound active in live cells. This study demonstrates that large, diverse cyclic peptide libraries can enable the discovery of cell-permeable PPI inhibitors from the ground up, providing a way to harness the powerful modality of small cyclic peptides to address often difficult-to-target intracellular interactions.
