Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery

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Item Type:	Article
Title:	Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery
Creators Name:	Dithmer, S., Staat, C., Müller, C., Ku, M.C., Pohlmann, A., Niendorf, T., Gehne, N., Fallier-Becker, P., Kittel, Á., Walter, F.R., Veszelka, S., Deli, M.A., Blasig, R., Haseloff, R.F., Blasig, I.E. and Winkler, L.
Abstract:	The blood-brain barrier (BBB) formed by the microvascular endothelium limits cerebral drug delivery. The paraendothelial cleft is sealed by tight junctions (TJs) with a major contribution from claudin-5, which we selected as a target to modulate BBB permeability. For this purpose, drug-enhancer peptides were designed based on the first extracellular loop (ECL) of claudin-5 to allow transient BBB permeabilization. Peptidomimetics (C5C2 and derivatives, nanomolar affinity to claudin-5) size-selectively (≤40 kDa) and reversibly (12-48 h) increased the permeability of brain endothelial and claudin-5-transfected epithelial cell monolayers. Upon peptide uptake, the number of TJ strand particles diminished, claudin-5 was downregulated and redistributed from cell-cell contacts to the cytosol, and the cell shape was altered. Cellular permeability of doxorubicin (cytostatic drug, 580 Da) was enhanced after peptide administration. Mouse studies (3.5 {mu}mol/kg i.v.) confirmed that, for both C5C2 and a d-amino acid derivative, brain uptake of Gd-diethylene-triamine penta-acetic acid (547 Da) was enhanced within 4 h of treatment. On the basis of our functional data, circular dichroism measurements, molecular modeling, and docking experiments, we suggest an association model between {beta}-sheets flanked by {alpha}-helices, formed by claudin-5 ECLs, and the peptides. In conclusion, we identified claudin-5 peptidomimetics that improve drug delivery through endothelial and epithelial barriers expressing claudin-5.
Keywords:	Tissue Barrier, Blood-Brain Barrier, Cell-Cell Contact, Tight Junction, Claudin Protein Family, Peptide, Animals, Mice, Rats
Source:	Annals of the New York Academy of Sciences
ISSN:	0077-8923
Publisher:	New York Academy of Sciences
Volume:	1397
Number:	1
Page Range:	169-184
Date:	June 2017
Official Publication:	https://doi.org/10.1111/nyas.13359
PubMed:	View item in PubMed

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