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

Shinya Ito, Koji Ogawa, Koh Takeuchi, Motoki Takagi, Masahito Yoshida, Takatsugu Hirokawa, Shoshiro Hirayama, Kazuo Shin-ya, Ichio Shimada, Takayuki Doi, Naoki Goshima, Tohru Natsume, Kazuhiro Nagata

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)20076-20085
Number of pages10
JournalJournal of Biological Chemistry
Volume292
Issue number49
DOIs
Publication statusPublished - 2017 Dec 8

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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