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J Biol Chem. 2017 Dec 8;292(49):20076-20085. doi: 10.1074/jbc.M117.815936. Epub 2017 Oct 12.

A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis.

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From the Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 603-8555.
the Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507.
the National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064.
the Japan Biological Informatics Consortium (JBIC), Tokyo 135-0064.
the Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578.
the Laboratory of Protein Metabolism and.
Division of Physical Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033.
the National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064,
From the Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto 603-8555,
the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan, and.
the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Kyoto 603-8555, Japan.


Fibrosis can disrupt tissue structure and integrity and impair organ function. Fibrosis is characterized by abnormal collagen accumulation in the extracellular matrix. Pharmacological inhibition of collagen secretion therefore represents a promising strategy for the management of fibrotic disorders, such as liver and lung fibrosis. Hsp47 is an endoplasmic reticulum (ER)-resident collagen-specific molecular chaperone essential for correct folding of procollagen in the ER. Genetic deletion of Hsp47 or inhibition of its interaction with procollagen interferes with procollagen triple helix production, which vastly reduces procollagen secretion from fibroblasts. Thus, Hsp47 could be a potential and promising target for the management of fibrosis. In this study, we screened small-molecule compounds that inhibit the interaction of Hsp47 with collagen from chemical libraries using surface plasmon resonance (BIAcore), and we found a molecule AK778 and its cleavage product Col003 competitively inhibited the interaction and caused the inhibition of collagen secretion by destabilizing the collagen triple helix. Structural information obtained with NMR analysis revealed that Col003 competitively binds to the collagen-binding site on Hsp47. We propose that these structural insights could provide a basis for designing more effective therapeutic drugs for managing fibrosis.


HSP47; collagen; drug screening; endoplasmic reticulum (ER); fibrosis; heat-shock protein (HSP); molecular chaperone; protein-protein interaction; serpinH1

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