Small-molecule proteostasis regulators for protein conformational diseases

Barbara Calamini, Maria Catarina Silva, Franck Madoux, Darren M. Hutt, Shilpi Khanna, Monica A. Chalfant, S. Adrian Saldanha, Peter Hodder, Bradley D. Tait, Dan Garza, William E. Balch, Richard I. Morimoto*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)185-196
Number of pages12
JournalNature Chemical Biology
Volume8
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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