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Small-molecule proteostasis regulators for protein conformational diseases
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Journal Article
Small-molecule proteostasis regulators for protein conformational diseases
2011
Overview
Screens of large compound libraries identify new small–molecule proteostasis regulators that, by enhancing the activity of the heat shock response factor HSF–1 and by activating other components of the proteostasis network, such as the antioxidant response or the unfolded protein response pathways, restore protein folding in multiple models of protein conformational diseases.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aging
/ Animals
/ Chemistry and Materials Science
/ Disease
/ DNA-Binding Proteins - drug effects
/ Drug Evaluation, Preclinical
/ Forkhead Transcription Factors - drug effects
/ Heat Shock Transcription Factors
/ Humans
/ Molecular Chaperones - drug effects
/ NF-E2-Related Factor 2 - drug effects
/ Protein Conformation - drug effects
/ Proteostasis Deficiencies - drug therapy
/ Rats
