Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder

Berselli, A.; Trevisani, M.; Alberini, G.; Pastore, A.; Di Fonzo, A.; Armirotti, A.; Castagnola, V.; Maragliano, L.; Benfenati, F.

doi:10.64898/2026.09.12.751133

bioRxiv · 10.64898/2026.09.12.751133

Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder

Berselli, A.·Trevisani, M.·Alberini, G.·Pastore, A.·Di Fonzo, A.·Armirotti, A.·Castagnola, V.·Maragliano, L.·Benfenati, F.

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Abstract

The blood-brain barrier (BBB) is a specialized interface that tightly regulates the exchange of molecules between the bloodstream and the brain. Its barrier function relies on a monolayer of brain endothelial cells sealed by tight junctions (TJs) that restrict paracellular flux through claudin-5 (CLDN5) multimeric complexes. To improve the delivery of nutrients and drugs to the brain, CLDN5-competitive peptides are promising carriers for creating size-controlled, temporary openings in the paracellular pathway. Here, we combine generative protein design and atomistic simulations to design ST9, a peptide with high nanomolar affinity for CLDN5. Compared with f1-C5C2, a CLDN5-binding peptide that we previously reported, ST9 induces a rapid, transient, size-controlled, and fully reversible increase in paracellular permeability, without altering CLDN5 expression or the proteomic profile of brain endothelial cells, indicating distinct mechanisms of TJ destabilization. This work provides a promising approach for developing next-generation BBB-opening agents to effectively treat neurological diseases.

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Berselli, A., Trevisani, M., Alberini, G., Pastore, A., Di Fonzo, A., Armirotti, A., Castagnola, V., Maragliano, L., Benfenati, F.. 2026-09-18. Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder. https://doi.org/10.64898/2026.09.12.751133

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