Small-molecule proteostasis regulators for protein conformational diseases

Nat Chem Biol. 2011 Dec 25;8(2):185-96. doi: 10.1038/nchembio.763.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Cell Line
  • DNA-Binding Proteins / drug effects
  • Drug Evaluation, Preclinical*
  • Forkhead Transcription Factors / drug effects
  • Heat Shock Transcription Factors
  • Homeostasis / drug effects
  • Humans
  • Molecular Chaperones / drug effects*
  • NF-E2-Related Factor 2 / drug effects
  • Protein Conformation / drug effects
  • Proteins / chemistry
  • Proteins / drug effects*
  • Proteins / physiology
  • Proteostasis Deficiencies / drug therapy*
  • Rats
  • Transcription Factors / drug effects*


  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Hsf1 protein, rat
  • Molecular Chaperones
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Proteins
  • Transcription Factors