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Small-molecule proteostasis regulators for protein conformational diseases

Academic Article
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Overview

authors

  • Calamini, B.
  • Silva, M. C.
  • Madoux, F.
  • Hutt, D. M.
  • Khanna, S.
  • Chalfant, M. A.
  • Saldanha, S. A.
  • Hodder, Peter
  • Tait, B. D.
  • Garza, D.
  • Balch, William E.
  • Morimoto, R. I.

publication date

  • February 2012

journal

  • Nature Chemical Biology  Journal

abstract

  • Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.

subject areas

  • Animals
  • Caenorhabditis elegans
  • Cell Line
  • DNA-Binding Proteins
  • Drug Evaluation, Preclinical
  • Forkhead Transcription Factors
  • Homeostasis
  • Humans
  • Molecular Chaperones
  • NF-E2-Related Factor 2
  • Protein Conformation
  • Proteins
  • Proteostasis Deficiencies
  • Rats
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC3262058

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.763

PubMed ID

  • 22198733
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Additional Document Info

start page

  • 185

end page

  • 196

volume

  • 8

issue

  • 2

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