Because many peptide and peptide-mimetic drugs are substrates of peptide transporter 1, it is important to evaluate the peptide transporter 1-mediated intestinal absorption of drug candidates in the early phase of drug development. Although intestinal cell lines treated with inhibitors of peptide transporter 1 are widely used to examine whether drug candidates are substrates for peptide transporter 1, these inhibitors are not sufficiently specific for peptide transporter 1. In this study, to generate a more precise evaluation model, we established peptide transporter 1-knockout induced pluripotent stem cells (iPSCs) by using a CRISPR-Cas9 system and differentiated the cells into intestinal epithelial-like cells. The permeability value and uptake capacity of glycylsarcosine (substrate of peptide transporter 1) in peptide transporter 1-knockout intestinal epithelial-like cells were significantly lower than those in wild-type intestinal epithelial-like cells, suggesting that peptide transporter 1 was successfully depleted in the epithelial cells. Taken together, our model can be useful in the development of peptide and peptide-mimetic drugs.

中文翻译：

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用于肠道药物吸收研究的SLC15A1 / PEPT1-基因敲除人诱导多能干细胞系的建立。

由于许多肽和模拟肽药物是肽转运蛋白1的底物，因此在药物开发的早期阶段，评估肽转运蛋白1介导的候选药物对肠道的吸收非常重要。尽管用肽转运蛋白1抑制剂处理的肠道细胞系已广泛用于检查候选药物是否是肽转运蛋白1的底物，但这些抑制剂对肽转运蛋白1的特异性还不够。在本研究中，我们将生成更精确的评估模型，通过使用CRISPR-Cas9系统建立了多肽转运蛋白1敲除诱导的多能干细胞（iPSC），并将其分化为肠上皮样细胞。肽转运蛋白1-基因敲除肠上皮样细胞中的糖基肌氨酸（肽转运蛋白1的底物）的通透性值和吸收能力显着低于野生型肠上皮样细胞中的值，这表明肽转运蛋白1已成功地被耗尽。上皮细胞。综上所述，我们的模型可用于开发肽和拟肽药物。