Blood-Brain Barrier (BBB)
A highly selective membrane of tightly joined endothelial cells lining brain blood vessels that controls which substances enter the brain. The BBB excludes most peptides, which is a major challenge for neurological peptide therapeutics. Difelikefalin was deliberately designed not to cross the BBB.
Technical Context
BBB structure: brain endothelial cells connected by tight junctions (claudins, occludins, ZO proteins — creating paracellular resistance ~1800 Ω·cm²), surrounded by pericytes (providing structural support and regulating endothelial function) and astrocyte end-feet (inducing and maintaining BBB properties). Transport across BBB: transcellular lipophilic pathway (small lipophilic molecules passively diffuse — rule: MW <400 Da and <8 hydrogen bonds for significant BBB penetration), carrier-mediated transport (glucose via GLUT1, amino acids via LAT1), receptor-mediated transcytosis (transferrin receptor, LRP1 — exploited for drug delivery), and adsorptive transcytosis (cationic molecules). Most peptides are excluded because they are too large, too hydrophilic, and lack specific transporters. BBB drug delivery strategies for peptides: intranasal delivery (olfactory/trigeminal nerve pathways), receptor-targeting conjugates (transferrin receptor-binding peptides), cell-penetrating peptide conjugates, focused ultrasound BBB disruption, and nanoparticle encapsulation. Difelikefalin was deliberately designed with properties preventing BBB penetration (D-amino acid, high polarity) to restrict effects to the periphery.