Development of a Novel Gene Silencer Pyrrole–Imidazole Polyamide Targeting Human Connective Tissue Growth Factor
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概要
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Pyrrole–imidazole (PI) polyamide can bind to specific sequences in the minor groove of double-helical DNA and inhibit transcription of the genes. We designed and synthesized a PI polyamide to target the human connective tissue growth factor (hCTGF) promoter region adjacent to the Smads binding site. Among coupling activators that yield PI polyamides, 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU) was most effective in total yields of PI polyamides. A gel shift assay showed that a PI polyamide designed specifically for hCTGF (PI polyamide to hCTGF) bound the appropriate double-stranded oligonucleotide. A fluorescein isothiocyanate (FITC)-conjugated PI polyamide to CTGF permeated cell membranes and accumulated in the nuclei of cultured human mesangial cells (HMCs) and remained there for 48 h. The PI polyamide to hCTGF significantly decreased phorbol 12-myristate acetate (PMA)- or transforming growth factor-β1 (TGF-β1)-stimulated luciferase activity of the hCTGF promoter in cultured HMCs. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated expression of hCTGF mRNA in a dose-dependent manner. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated levels of hCTGF protein in HMCs. These results indicate that the developed synthetic PI polyamide to hCTGF could be a novel gene silencer for fibrotic diseases.
- 公益社団法人 日本薬学会の論文
著者
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Ueno Takahiro
Advanced Res. Inst. For The Sci. And Humanities Nihon Univ.
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Ueno Takahiro
Division Of Nephrology Hypertension And Endocrinology Department Of Medicine Nihon University School
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Fukuda Noboru
Advanced Research Institute Of Science And Humanities Nihon University
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Fukuda Noboru
Advanced Res. Inst. For The Sci. And Humanities Nihon Univ.
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Fukuda Noboru
日本大学 総合科学研究科
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Fukuda Noboru
The 2nd Department Of Internal Medicine Nihon University School Of Medicine
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Matsumoto Yoshiaki
Department Of Clinical Pharmacology And Toxicology Showa Pharmaceutical University
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Fukuda Noboru
Division Of Nephrology And Endocrinology Department Of Medicine Nihon University School Of Medicine
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Matsumoto Koichi
Division Of Nephrology And Endocrinology Department Of Medicine Nihon University School Of Medicine
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Watanabe Takayoshi
Division Of Cancer Genetics Department Of Advanced Medical Science Nihon University School Of Medici
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MATSUDA Hiroyuki
Advanced Research Institute for the Science and Humanities, Nihon University
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NAGASE Hiroki
Advanced Research Institute for the Science and Humanities, Nihon University
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Wan Jian-Xin
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, School of Medicine, N
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Saito Kosuke
Advanced Research Institute of the Sciences and Humanities, Nihon University
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Matsumoto Yoshiaki
Department Of Clinical Pharmacokinetics College Of Pharmacy Nihon University
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Matsuda Hiroyuki
Advanced Research Institute For The Science And Humanities Nihon University
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Wan Jian-Xin
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University
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Fukuda Noboru
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, School of Medicine, Nihon University
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Watanabe Takayoshi
Division of Cancer Genetics, Department of Advanced Medical Science, School of Medicine, Nihon University
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Fukuda Noboru
Division of Life Science, Advanced Research Institute of the Sciences and Humanities, Nihon University Graduate School
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Ueno Takahiro
Division of Nephrology and Endocrinology, Department of Medicine, Nihon University School of Medicine
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