Abstract
Protein folding in the cell is a complex process with a fine balance between productive and non-productive folding. To modulate, either up-regulating or down-regulating, the level of one specific protein with multiple approaches is possible, including the modulation of catalysed protein folding, the use of chemical and pharmacological chaperones, alteration of natural protein-protein interactions, the regulation of degradative pathways and manipulation of natural control mechanisms, such as the heat shock response and the unfolded protein response. Errors in proteostasis are linked to a wide range of disease states and many examples exist of the successful manipulation of proteostasis for the partial or complete elimination of the disease phenotype, including for many amyloid based diseases such as Parkinsons and Alzheimers as as well as for loss-of-function diseases such as Fabrys and Gauchers diseases. This review takes an overview of the different approaches that can be used to alter proteostasis with an emphasis on peptidomimetic inhibitors and activators of protein folding. It covers the modulators available, their mechanisms of action and potential limitations, including the problems of specificity in altering proteostasis.
Keywords: Proteostasis, protein folding, peptidomimetic, pharmacological chaperone, chemical chaperone, molecular chaperone, degradation
Current Pharmaceutical Design
Title: Modulating Proteostasis: Peptidomimetic Inhibitors and Activators of Protein Folding
Volume: 15 Issue: 21
Author(s): Feras Hatahet and Lloyd W. Ruddock
Affiliation:
Keywords: Proteostasis, protein folding, peptidomimetic, pharmacological chaperone, chemical chaperone, molecular chaperone, degradation
Abstract: Protein folding in the cell is a complex process with a fine balance between productive and non-productive folding. To modulate, either up-regulating or down-regulating, the level of one specific protein with multiple approaches is possible, including the modulation of catalysed protein folding, the use of chemical and pharmacological chaperones, alteration of natural protein-protein interactions, the regulation of degradative pathways and manipulation of natural control mechanisms, such as the heat shock response and the unfolded protein response. Errors in proteostasis are linked to a wide range of disease states and many examples exist of the successful manipulation of proteostasis for the partial or complete elimination of the disease phenotype, including for many amyloid based diseases such as Parkinsons and Alzheimers as as well as for loss-of-function diseases such as Fabrys and Gauchers diseases. This review takes an overview of the different approaches that can be used to alter proteostasis with an emphasis on peptidomimetic inhibitors and activators of protein folding. It covers the modulators available, their mechanisms of action and potential limitations, including the problems of specificity in altering proteostasis.
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Cite this article as:
Hatahet Feras and Ruddock W. Lloyd, Modulating Proteostasis: Peptidomimetic Inhibitors and Activators of Protein Folding, Current Pharmaceutical Design 2009; 15 (21) . https://dx.doi.org/10.2174/138161209788682343
DOI https://dx.doi.org/10.2174/138161209788682343 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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