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Updated: Jul 19, 2026
Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
Published on: July 21, 2021
Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs
Tsutomu Arakawa1, Daisuke Ejima, Yoshiko Kita
1Alliance Protein Laboratories, Thousand Oaks, CA 91360, USA.
Abstract:
A great deal of attention has been paid to so-called amyloid diseases, in which the proteins responsible for the cell death and resultant diseases undergo conformational changes and aggregate in vivo, although whether aggregate formation is the cause or the result of the cell death is controversial. Recently, an increasing attention is given to protein folding diseases tightly associated with mutations. These mutations result in temperature-dependent misfolding and hence inactivation of the proteins, leading to loss of function, at physiological temperature; at low so-called permissive temperatures, the mutant proteins correctly fold and acquire functional structure. Alternatively, activation can be induced by use of osmolytes, which restores the folding of the mutant proteins and hence are called chemical chaperones. The osmolytes are compatible with macromolecular function and do stabilize the native protein structure. However, chemical chaperones require high concentrations for effective folding of mutant proteins and hence are too toxic in in-vivo applications. This limitation can be overcome by pharmacological chaperones, whose functions are similar to the chemical chaperones, but occur at much lower concentrations, i.e., physiologically acceptable concentrations. Although the research and clinical importance of pharmacological chaperones has been emphasized, the initial and central concept of osmolytes is largely ignored. Here we attempt to bridge the concept of osmolytes to applications of pharmacological chaperones.
Insights
This study explores how osmolytes, or chemical chaperones, can help misfolded proteins regain function. It bridges the concept of osmolytes to pharmacological chaperones for potential therapeutic applications in protein folding diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Protein Misfolding Diseases
Background:
- Amyloid diseases and protein folding diseases involve protein misfolding and aggregation.
- Mutations can cause temperature-dependent protein misfolding, leading to loss of function at physiological temperatures.
- Osmolytes (chemical chaperones) can restore protein folding but require high, toxic concentrations.
Purpose of the Study:
- To bridge the concept of osmolytes to the application of pharmacological chaperones.
- To explore how osmolytes can inform the development of safer and more effective protein folding disease treatments.
Main Methods:
- Review and conceptual analysis of osmolytes and chemical chaperones.
- Comparison of chemical chaperones with pharmacological chaperones.
- Exploration of the link between osmolyte principles and pharmacological chaperone mechanisms.
Main Results:
- Osmolytes stabilize native protein structures and are compatible with macromolecular function.
- Pharmacological chaperones offer similar benefits to chemical chaperones at lower, non-toxic concentrations.
- The foundational concept of osmolytes is often overlooked in current research on pharmacological chaperones.
Conclusions:
- Understanding osmolytes is crucial for advancing the application of pharmacological chaperones.
- Pharmacological chaperones represent a promising therapeutic strategy for protein folding diseases by overcoming the limitations of chemical chaperones.
- Bridging osmolyte concepts with pharmacological chaperone applications may lead to novel treatments for debilitating diseases.
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