Establishment of SLC15A1/PEPT1-Knockout Human-Induced Pluripotent Stem Cell Line for Intestinal Drug Absorption Studies
| Autor: | Moe Ichikawa, Hiroyuki Mizuguchi, Sayaka Deguchi, Kazuo Harada, Ryosuke Negoro, Kazuo Takayama, Kazumasa Hirata, Tomoki Yamashita, Kanae Kawai |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Drug lcsh:QH426-470 media_common.quotation_subject Peptide Article human iPS cells Intestinal absorption 03 medical and health sciences 0302 clinical medicine Genetics intestinal epithelial-like cells genome editing CRISPR PEPT1 lcsh:QH573-671 Induced pluripotent stem cell Molecular Biology media_common chemistry.chemical_classification drug absorption biology lcsh:Cytology Chemistry Peptide transporter 1 Transporter drug transporter Cell biology lcsh:Genetics 030104 developmental biology Drug development 030220 oncology & carcinogenesis biology.protein Molecular Medicine SLC15A1 CRISPR-Cas9 |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 49-57 (2020) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2019.11.008 |
| Popis: | 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. Graphical Abstract |
| Databáze: | OpenAIRE |
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