Paracellular Channel as Drug Target

Abstract The concept of “druggable” tight junction, i.e. with drugs to modulate the paracellular permeability, dates back to pre-molecular biology era. There is a strong medical need to develop drugs that can increase the paracellular permeability in vital organs such as the blood-brain barrier, the intestine, the kidney, and so on. Small chemicals such as calcium chelator, sodium caprate and chitosan, and cytokines such as histamine, bradykinin and tumor necrosis factor alpha, and proteases such as trypsin, prostasin and matrix metalloproteases, have been exploited as potential paracellular channel modulators in various cell or organ systems. These approaches, while effective under certain circumstances, lack the specificity to tight junction since they must act through intracellular signaling pathways that will inevitably perturb many other aspects of cellular function. Several natural toxins have been found to bind to tight junction proteins, dismantle tight junction architecture, and alter paracellular permeability. Structural studies of claudins bound to Clostridium perfringens enterotoxin provide three-dimensional information of the molecular interfaces between toxin and claudin. Synthetic peptides designed to mimic the extracellular domain structures of claudins or other tight junction proteins may interfere with the molecular interactions important for tight junction integrity and prove to be a more selective class of paracellular channel modulators.