Claudin peptidomimetics modulate tissue barriers for enhanced drug delivery


  • S. Dithmer
  • C. Staat
  • C. Müller
  • M.C. Ku
  • A. Pohlmann
  • T. Niendorf
  • N. Gehne
  • P. Fallier-Becker
  • Á. Kittel
  • F.R. Walter
  • S. Veszelka
  • M.A. Deli
  • R. Blasig
  • R.F. Haseloff
  • I.E. Blasig
  • L. Winkler


  • Annals of the New York Academy of Sciences


  • Ann N Y Acad Sci 1397 (1): 169-184


  • 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.