Generation of membrane-permeable cyclic peptides inhibiting protein-protein interaction.
Cyclic peptides just got a major upgrade. Researchers at EPFL in Switzerland have shown you can generate membrane-permeable cyclic peptides that block protein-protein interactions—no natural starting points required. This isn’t just another tweak on old scaffolds. They built and screened a fully random library of over 15,000 cyclic peptides, all at nanomole scale, targeting the notoriously tough Keap1-Nrf2 interaction. The result: a potent, cell-permeable inhibitor that works in live cells.
Nat Chem Biol
by Ji X, Farrera-Soler L, Li J et al.
“Generation of membrane-permeable cyclic peptides inhibiting protein-protein interaction. Ji X(#)(1), Farrera-Soler L(#)(1), Li J(1), Sangouard G(1), De Sadeleer N(1), Nielsen AL(1), Mothukuri GK(1), Zarda A(1), Will EJ(1), Pojer F(2), Lau K(2), Heinis C(3). Author information: (1)Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. (2)Protein Production and Structure Core Facility (PTPSP), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. (3)Institute of Chemical Sciences and Engineering, School of Basic Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. christian.heinis@epfl.ch. (#)Contributed equally 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. © 2026. The Author(s), under exclusive licence to Springer Nature America, Inc. Conflict of interest statement: Competing interests: C.H. is a cofounder of the spinoff company Orbis Medicines. The other authors declare no competing interests.”
Key takeaway: You don’t need to start with known ligands or fragments to find effective cyclic peptide inhibitors for challenging intracellular targets. Build a big, diverse library, screen it, and optimize fast. The EPFL team did rapid design-build-test cycles to dial in both binding and membrane permeability.
Why does this matter for peptide research?
Most protein-protein interactions are considered “undruggable” by traditional small molecules
Cyclic peptides combine the specificity of biologics with the cell penetration of small molecules
This approach enables de novo discovery—no more waiting for a lucky natural product hit
For researchers interested in hitting tough intracellular targets, this opens the door to a new generation of peptide tools. The technique is scalable and doesn’t rely on prior knowledge of binding motifs. It’s a solid proof-of-concept for leveraging large, random peptide libraries in the hunt for functional PPI inhibitors.
If you want to dig deeper into how cyclic peptides are changing the game, check out the peptide research index for more groundbreaking studies.
Bottom line: Membrane-permeable cyclic peptides are now a practical reality, not just an academic dream. This is a big win for anyone pushing the boundaries of peptide research.
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