Abstract
The tight junction (TJ) is an intercellular sealing component found in epithelial and endothelial tissues that regulates the passage of solutes across the paracellular space. Research examining the biology of TJs has revealed that they are complex biochemical structures constructed from a range of proteins including claudins, occludin, tricellulin, angulins and junctional adhesion molecules. The transient disruption of the barrier function of TJs to open the paracellular space is one means of enhancing mucosal and transdermal drug absorption and to deliver drugs across the blood–brain barrier. However, the disruption of TJs can also open the paracellular space to harmful xenobiotics and pathogens. To address this issue, the strategies targeting TJ proteins have been developed to loosen TJs in a size- or tissue-dependent manner rather than to disrupt them. As several TJ proteins are overexpressed in malignant tumors and in the inflamed intestinal tract, and are present in cells and epithelia conjoined with the mucosa-associated lymphoid immune tissue, these TJ-protein-targeted strategies may also provide platforms for the development of novel therapies and vaccines. Here, this paper reviews two TJ-protein-targeted technologies, claudin binders and an angulin binder, and their applications in drug development.
Highlights
The boundaries between the inside of the body and the outside environment in the airway and gastrointestinal tract, and between the systemic circulation and tissues in the brain, eye, testis, and placenta, are separated by epithelial and endothelial cell sheets, respectively
tight junction (TJ) control the diffusion of ions, solutes, and water across the paracellular space to maintain homeostasis, and the loss of TJ integrity appears to be associated with the development of intestinal diseases [2,3], atopic dermatitis [4], and psychiatric disorders [5,6]
Claudins were identified in 1998 as components of TJ strands that are crucial for the sealing of the intercellular space [19]
Summary
The boundaries between the inside of the body and the outside environment in the airway and gastrointestinal tract, and between the systemic circulation and tissues in the brain, eye, testis, and placenta, are separated by epithelial and endothelial cell sheets, respectively. TJs prevent mucosal and epidermal absorption of drugs and the delivery of drugs from the systemic circulation to the brain, eye, testis, and placenta. A freeze-fracture replica electron microscopy analysis has shown that TJs consist of a meshwork of proteins called TJ strands [7]. In epithelial cells, these TJ strands are located at the apical side of the lateral membrane. Tricellular TJs seal the tubular structure created at tricellular contacts by the three vertically extending TJ strands and the three adjoining cell membranes [14]. A modulation of the structure of TJs to loosen the paracellular space can be used to increase mucosal and epidermal drug absorption, as well as drug delivery to the brain. The efficacy and safety of claudin and angulin binders for the development of TJ-directed drugs is reviewed
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