Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis |
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| Authors: | Dr Daisuke Okuno Dr Noriho Sakamoto Dr Mohammed S O Tagod Yoshiko Akiyama Dr Sakiko Moriyama Dr Takuto Miyamura Dr Atsuko Hara Dr Takashi Kido Dr Hiroshi Ishimoto Prof Yuji Ishimatsu Prof Takashi Tanaka Prof Jun Ishihara Prof Kohsuke Takeda Prof Yoshimasa Tanaka Prof Hiroshi Mukae |
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| Affiliation: | 1. Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8501 Japan;2. Center for Medical Innovation, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588 Japan;3. Department of Nursing, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8520 Japan;4. Department of Natural Product Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521 Japan;5. Department of Pharmaceutical Organic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521 Japan;6. Department of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521 Japan |
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| Abstract: | Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis. |
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| Keywords: | heat shock protein 47 inhibitors fibril formation assay idiopathic pulmonary fibrosis natural products drug discovery |
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