New Peptides Slip Into Cells to Block Hard-to-Target Proteins

Key Takeaways

• EPFL screened 15,360 synthetic cyclic peptides for cell permeability.
• Peptide 30 (890 Da) effectively blocks Keap1‑Nrf2 inside living cells.
• Non‑polar, low‑polar‑surface design enables membrane crossing without charge.
• Orbis Medicines secured ~€90 million ($98 million) to commercialize the platform.

Pulse Analysis

Targeting protein‑protein interactions (PPIs) inside cells has remained a formidable challenge because traditional small‑molecule drugs lack the surface area to engage the flat, extensive interfaces that drive many disease pathways. Peptides, especially cyclic variants, can cover larger interaction surfaces, but their inability to cross lipid bilayers has limited clinical use, relegating most peptide drugs to injection. Recent advances in peptide chemistry aim to reconcile potency with permeability, a balance essential for expanding the therapeutic toolbox beyond extracellular targets.

The EPFL team, led by Christian Heinis, tackled this dilemma by engineering a library of 15,360 small, non‑polar cyclic peptides designed for membrane entry. Using high‑throughput synthesis and nanomole‑scale screening, they isolated peptide 30, a 890‑Dalton molecule that not only traverses cellular membranes but also disrupts the Keap1‑Nrf2 interaction—a pathway implicated in oxidative stress, inflammation, and oncogenesis. Structural analysis revealed that peptide 30 binds Keap1 at a distinct site from native Nrf2, demonstrating that synthetic cyclic peptides can achieve both high affinity and unique binding modes while maintaining drug‑like physicochemical properties.

The broader implication is a new paradigm for drug discovery: a platform that can generate cell‑permeable peptide inhibitors without starting from existing ligands or natural products. This could accelerate the development of oral peptide medicines, a segment that has historically struggled with bioavailability. Orbis Medicines, the spin‑off commercializing the technology, has secured roughly €90 million ($98 million) in Series A funding, underscoring investor confidence. With plans to target high‑profile PPIs such as KRAS, β‑catenin, and c‑Myc, the platform may reshape pipelines for oncology and neurodegeneration, offering a competitive edge in a market hungry for novel intracellular therapeutics.