Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder
- 1Istituto Italiano di Tecnologia
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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BibTeX
@misc{berselli2026controlled,
title = {{Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder}},
author = {A. Berselli and M. Trevisani and G. Alberini and A. Pastore and A. Di Fonzo and A. Armirotti and V. Castagnola and L. Maragliano and F. Benfenati},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.12.751133},
url = {https://www.biorxiv.org/content/10.64898/2026.09.12.751133v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Controlled Blood-Brain Barrier Modulation by a High-Affinity Claudin-5 Peptide Binder
AU - A. Berselli
AU - M. Trevisani
AU - G. Alberini
AU - A. Pastore
AU - A. Di Fonzo
AU - A. Armirotti
AU - V. Castagnola
AU - L. Maragliano
AU - F. Benfenati
PY - 2026
DA - 2026/09/12
PB - bioRxiv
DO - 10.64898/2026.09.12.751133
UR - https://www.biorxiv.org/content/10.64898/2026.09.12.751133v1
AB - 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.
ER -