A claudin5-binding peptide enhances the permeability of the blood-brain barrier in vitro
The blood-brain barrier (BBB) maintains brain homeostasis but also prevents most drugs from entering the brain. No paracellular diffusion of solutes is allowed because of tight junctions that are made impermeable by the expression of claudin5 (CLDN5) by brain endothelial cells. The possibility of regulating the BBB permeability in a transient and reversible fashion is in strong demand for the pharmacological treatment of brain diseases. Here, we designed and tested short BBB-active peptides, derived from the CLDN5 extracellular domains and the CLDN5-binding domain of <i>Clostridium perfringens</i> enterotoxin, using a robust workflow of structural modeling and in vitro validation techniques. Computational analysis at the atom level based on solubility and affinity to CLDN5 identified a CLDN5-derived peptide not reported previously called f1-C5C2, which was soluble in biological media, displayed efficient binding to CLDN5, and transiently increased BBB permeability. The peptidomimetic strategy described here may have potential applications in the pharmacological treatment of brain diseases.
Authors
- Martina Trevisani
- Silvia Vercellino (ORCID: https://orcid.org/0000-0002-9264-0915)
- Andrea Armirotti (ORCID: https://orcid.org/0000-0002-3766-8755)
- Alessandro Berselli (ORCID: https://orcid.org/0000-0002-2241-3530)
- Francesco Pisani (ORCID: https://orcid.org/0000-0001-8511-117X)
- Enrico Millo (ORCID: https://orcid.org/0000-0002-4019-0051)
- Luca Maragliano (ORCID: https://orcid.org/0000-0002-5705-6967)
- Clarissa Braccia (ORCID: https://orcid.org/0000-0002-6343-9614)
- Federico Zara (ORCID: https://orcid.org/0000-0001-9744-5222)
- Valentina Castagnola (ORCID: https://orcid.org/0000-0002-8651-5958)
- Fabio Benfenati (ORCID: https://orcid.org/0000-0002-0653-8368)
- Giulio Alberini (ORCID: https://orcid.org/0000-0003-2794-2084)
- Dinu Zinovie Ciobanu (ORCID: https://orcid.org/0009-0003-5528-9550)
- Veronica Cartocci
- Eleonora Centonze (ORCID: https://orcid.org/0000-0003-1802-6471)
Institutions
- Marche Polytechnic University (IT)
- Istituto Giannina Gaslini (IT)
- Italian Institute of Technology (IT)
- Ospedale Policlinico San Martino (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Bari Aldo Moro (IT)
- University of Genoa (IT)
Publication Details
- Journal
- Science Advances
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1126/sciadv.adq2616
- Citations
- 14
- Primary Topic
- Barrier Structure and Function Studies
- Type
- article
- Field-Weighted Citation Impact
- 11.79