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首页> 外文期刊>Biochemical Pharmacology >A claudin-4 modulator enhances the mucosal absorption of a biologically active peptide.
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A claudin-4 modulator enhances the mucosal absorption of a biologically active peptide.

机译：claudin-4调节剂可增强生物活性肽的粘膜吸收。

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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.
机译：肽，蛋白质和核酸等生物制剂是新兴的药物。穿过上皮是生物制剂吸收的第一步。紧密连接（TJ）充当相邻上皮细胞之间的密封，防止溶质自由穿过上皮。我们以前发现，当我们使用右旋糖酐作为模型药物，而产气荚膜梭菌肠毒素（C-CPE）的C末端片段用作claudin-时，调制关键的TJ成分claudin-4是提高空肠吸收的有效方法。 4个调制器。在这里，我们调查了claudin-4调节剂是否增强了生物制剂人甲状旁腺激素衍生物hPTH（1-34）的空肠，鼻和肺吸收。 claudin-4调节剂可增强hPTH（1-34）在鼻腔和空肠的吸收。 C-CPE是疏水性的，低溶解度小于0.3mg / ml，但是C-CPE N末端10个氨基酸的缺失将其溶解度提高了30倍。此外，与claudin-4结合的N端截短的C-CPE调节了TJ屏障并增强了葡聚糖的空肠吸收。 N端截断的C-CPE还增强了hPTH（1-34）的空肠和肺吸收。该报道是第一个表明claudin-4调节剂可能是肽药物的空肠，肺和鼻吸收的有希望的增强剂。

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