title: A claudin-4 modulator enhances the mucosal absorption of a biologically active peptide.
abstract: Biologics, such as peptides, proteins and nucleic acids, are emerging pharmaceuticals. Passage across the epithelium is the first step in the absorption of biologics. Tight junctions (TJ) function as seals between adjacent epithelial cells, preventing free movement of solutes across the epithelium. We previously found that modulation of a key TJ component, claudin-4, is a potent method to enhance jejunal absorption when we used dextran as a model drug and the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) as a claudin-4 modulator. Here, we investigated whether the claudin-4 modulator enhances jejunal, nasal and pulmonary absorption of a biologics human parathyroid hormone derivative, hPTH(1-34). The claudin-4 modulator enhanced nasal but not jejunal and pulmonary absorption of hPTH(1-34). C-CPE is hydrophobic with low solubility of less than 0.3mg/ml, but deletion of 10 amino acids at the N-terminal of C-CPE increased its solubility by 30-fold. Moreover, the N-terminal truncated C-CPE bound to claudin-4, modulated the TJ-barrier and enhanced jejunal absorption of dextran. The N-terminal-truncated C-CPE also enhanced jejunal and pulmonary absorption of hPTH(1-34). This report is the first to indicate that a claudin-4 modulator may be a promising enhancer of the jejunal, pulmonary and nasal absorption of a peptide drug.
authors.affiliation: Department of Biopharmaceuticals Research, Biopharma Center, Asubio Pharma Co., Ltd., Gunma, Japan. uchida.hiroshi.b3@asubio.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchida
authors.forename: Masuo
authors.initials: M
authors.lastname: Kondoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hanada
authors.forename: Azusa
authors.initials: A
authors.lastname: Takahashi
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Yagi
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000818:Animals; D018938:Caco-2 Cells; D062506:Claudin-4; D003911:Dextrans / Q000378:metabolism; D004768:Enterotoxins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000502:physiology; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000502:physiology; D009297:Nasal Mucosa / Q000187:drug effects* / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000502:physiology; D020349:Surface Plasmon Resonance; D019379:Teriparatide / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; D003911:Dextrans; D004768:Enterotoxins; D008565:Membrane Proteins; D010455:Peptides; C035598:enterotoxin, Clostridium; D019379:Teriparatide