In medicine, the source of all good research is the clear identification of “the problem” and an unequivocal offering of “the solution.” 

“Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases,” Tran and colleagues wrote in Molecules. 

To understand why proteins are so vulnerable to disruption in their original shape, we need to first examine one of the fundamental properties of protein: its tridimensional architecture. This unique structure of proteins and any biological foldings that take place are highly-regulated events and are important for native biological trafficking, functions, and characteristics. 

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The proteostasis network is responsible for protein folding, along with their eventual trafficking and degradation. If protein folding took place in a factory, the proteostasis network would be best described as the “quality control team.” 

In the process of regulating the folding and trafficking of protein, there is little room for error. Hence, we are introduced to another category of molecules, known as molecular chaperone proteins, which assist misfolded proteins and prevent them from aggregating. 

“The biological concept of molecular chaperoning may be applied to help misfolded mutant proteins that retain some level of functionality escaping the cell quality control mechanism,” Tran and colleagues wrote. 

Back to our “factory” analogy, molecular chaperone proteins can be said to act as on-site inspectors that check for quality control violations that were missed by the proteostasis network. These molecules play an integral role in treating conformational diseases and work in synergy with the proteostasis network to get cells working and functioning at their optimum. In biology, “chaperones” refer to molecules that are able to help a protein recover its correct confirmation. 

The Experiment in Pharmacological Chaperones 

Molecular scientists have observed with great attention and no small degree of awe at how various systems in a cell work together to secure quality control in terms of the creation and function of proteins. In the early 2000s, a team of scientists decided to create and test the usage of pharmacological chaperones. 

“Unlike chemical chaperones, [pharmacological chaperones] are specific ligands that stabilize the correct conformation of misfolded proteins by selectively binding to them,” Tran and colleagues wrote. “In doing so, they escort the mutant protein to its normal cell location where it may express its residual level of function.” 

The word “chaperone” in itself has rich layers of meaning. In real life, a chaperone is someone who accompanies another person to complete a task; ie, a male doctor needing a female chaperone to accompany him when performing an intimate examination on a female patient. The word “chaperone” invokes the idea of teamwork, collaboration, and ensuring that the task is done according to the standards set. 

In Molecules, Borie-Guiochot and colleagues conducted a literature review in which they sought to better understand the various pharmacological chaperone therapies available for Pompe disease

The explosion in interest in the research world regarding pharmacological chaperone therapy has allowed researchers to adapt this therapy for various conditions, such as Gaucher disease and Fabry disease. Its adaptation for Pompe disease is admittedly slower due to the rarity of this condition. Nevertheless, scientists have identified 297 missense acid alpha-glucosidase (GAA) mutations that cause Pompe disease; these mutations account for around one-tenth of patients with Pompe disease who would be amenable to pharmacological chaperones. 

Read more about Pompe disease etiology 

The mainstay treatment for Pompe disease today is enzyme replacement therapy (ERT); it is therefore only reasonable for pharmacological chaperones to be compared with this mainstay treatment. Interestingly, pharmacological chaperones offer a number of benefits that ERT does not possess, namely: it has the advantage of having active ingredients that have a low molecular weight, it has greater bioavailability, and it can possibly cross the blood-brain barrier. 

“Moreover, the restoration of only 10–20% of protein activity would be, in most cases, enough to prevent clinical manifestations of the disease,” Borie-Guichot and colleagues wrote on the benefits of pharmacological chaperones. 

The first class of pharmacological chaperones consisted of active site-specific chaperones (ASSCs), which competitively inhibited protein used at concentrations below what was typically required for cellular inhibition. Various ASSCs have been characterized for a diverse range of conformational diseases. However, one of its most significant disadvantages is its inability to control the balance between protein inhibition and activation. 

A second class of pharmacological chaperones emerged soon after. These pharmacological chaperones are non-inhibitory; they merely increase residual enzyme activity. While studies have found this form of therapy promising, it is not commercially available at present. 

Studies indicate that pharmacological chaperones are best used to deal with the problem of missense mutations. It is important to note that the efficacy of pharmacological chaperones depends largely on the type of enzyme variant requiring correction. Researchers in this field describe how pharmacological chaperones may be able to improve enzyme stability and lysosomal trafficking and generate activity in cultured Pompe cells incubated with exogenous recombinant enzymes. 

Read more about Pompe disease treatment

“This consists of not increasing the residual activity of a mutant enzyme, but in increasing the efficiency of the recombinant enzymes used for ERT by combining ERT and [pharmacological chaperone therapy,” Borie-Guichot and colleagues wrote.

In summary, pharmacological chaperones offer real theoretical benefits in tackling genetic diseases such as Pompe disease at the root source of the problem, but it may take another few years for the research around this topic to reach a certain threshold of excellence and reproducibility before it receives widespread approval and clinical use.


Borie-Guichot M, Tran ML, Génisson Y, Ballereau S, Dehoux C. Pharmacological chaperone therapy for Pompe diseaseMolecules. Published online November 29, 2021. doi:10.3390/molecules26237223

Tran ML, Génisson Y, Ballereau S, Dehoux C. Second-generation pharmacological chaperones: beyond inhibitorsMolecules. Published online July 9, 2020. doi:10.3390/molecules25143145