Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

Abstract

The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…Small molecules, such as pharmacological chaperones (PCs) for missense variants and read-through therapies for nonsense variants, have been developed for other diseases and may also provide novel therapeutic means for SSADH-D. Below, we will briefly summarize these strategies and give examples of their use in other diseases. For a more detailed review on substances used for these purposes, we recommend the reviews by Liguori et al and Nagel-Wolfrum et al [118,119].…”

Co‐expression with chaperones can affect protein 3D structure as exemplified by loss‐of‐function variants of human prolidase

“…Nevertheless, several approaches have been investigated with some success [16]. One of the approaches was the development of so-called pharmaceutical chaperones [12], but to the best of our knowledge activation of natural protein chaperones as a way of stabilizing LOF enzymes has not been widely tested and such effect was never proved by means of structural biology.…”

“…In spite of this, one could envision that a drug molecule, such as for instance a shape-specific antibody, an aptamer or a small molecule, has a stabilizing effect on the native structure. In fact, such small molecular agents referred to as pharmaceutical chaperones [11] have been investigated for a number of targets related to protein misfolding [12,13] resulting in several drug candidates and approved drugs [14]. Yet, the development of such a stabilizing agent is usually a tedious project [11][12][13]15] and the utmost importance of structural biology was underlined in such investigations [16].…”

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…Small molecules such as pharmacological chaperones (PCs) for missense variants and readthrough therapies for nonsense variants have been developed for other diseases and may also provide novel therapeutic means for SSADH-D. Below, we will briefly summarize these strategies and give examples of their use in other diseases. For a more detailed review on substances used for these purposes, we recommend the reviews by Liguori et al and Nagel-Wolfrum et al [114,115].…”