A Method to Prepare a Bioprobe for Regulatory Science of the Drug Delivery System to the Brain: An Angulin Binder to Modulate Tricellular Tight Junction-Seal

The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies

“…Comparing bi- and tricellular contacts, it is concluded that the expressed amount of sealing TJ proteins (claudin-5 and -11) in bicellular TJs is about two orders of magnitude higher than that of tricellulin [ 50 ]. This suggests that the BBB function is quantitatively determined by two-cell TJs, which prevent permeation of small and large molecular weight compounds [ 63 ], rather than by tricellular TJs that withhold larger molecules [ 211 , 224 ].…”

“…Tricellulin and angulins form so-called central sealing elements [ 226 ] laterally in three-cell(-like) contacts ( Figure 2 C). For delivery of antisense oligonucleotides (5.3 kDa) through the BBB, these TJs can be modulated by recombinant angubindin-1, a Clostridium perfringens iota-toxin, which binds to angulin-1 [ 224 ]. Angulin-1 knockout mice exhibit embryonic lethality [ 227 ] with BBB failure [ 228 ], which is not known from tricellulin deficiency.…”

Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

“…Ib is composed of four domains consisting of 664 amino acids ( Figure 5 ) [ 102 ]. The three N-terminal domains of Ib play important roles in the organization of the Ib-pore, and the C-terminal domain IV of Ib (Ib421-664; 421–664 amino acids, ~30 kDa), named angubindin-1, binds to its receptors, angulin-1 and -3, but not to angulin-2 [ 103 , 104 , 105 ]. Angubindin-1 changed the localization of angulin-1 and tricellulin from tTJs to bTJs, thus increasing the permeability of TJs [ 104 ].…”