Journal
CHEMMEDCHEM
Volume 16, Issue 16, Pages 2515-2523Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202100064
Keywords
heat shock protein 47 inhibitors; fibril formation assay; idiopathic pulmonary fibrosis; natural products; drug discovery
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Funding
- Japanese Society for the Promotion of Science (JSPS KAKENHI) [20K08520]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED [JP20am0101088, 2262]
- Grants-in-Aid for Scientific Research [20K08520] Funding Source: KAKEN
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The study prepared human HSP47 and established an inhibitor screening system. Among the compounds screened, three were found to effectively inhibit the function of HSP47, with epigallocatechin-3-O-gallate from tea leaves being one of them.
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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