Pharmacological Chaperones: Potential Treatment for Conformational Diseases

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Title: Pharmacological Chaperones: Potential Treatment for Conformational Diseases
Authors: Bernier, Virginie; Lagace, Monique; Bichet, Daniel G.; Bouvier, Michel
Publisher: Trends in Pharmacological Sciences
Date Published: July 01, 2004
Reference Number: 655
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Abstract • Translation
Increasing numbers of inherited diseases are found to result from mutations that lead to misfolded proteins. In many cases, the changes in conformation are relatively modest and the function of the protein would not be predicted to be affected. Yet, these proteins are recognized as "misfolded" and degraded prematurely. Recently, small molecules known as chemical and pharmacological chaperones were found to stabilize such mutant proteins and facilitate their trafficking to their site of action. Here, we review the recent published evidence suggesting that pharmacological chaperones represent promising avenues for the treatment of endocrine and metabolic diseases such as hyperinsulinemic hypoglycemia, hypogonadotropic hypogonadism and nephrogenic diabetes insipidus, and might become a general therapeutic strategy for the treatment of conformational diseases.

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)


In biochemistry, the term conformation refers to the particular shape of something. For example, each type of protein has a particular conformation. Conformational diseases occur when a biological substance, e.g., a protein, does not have the shape it should. Conformational diseases occur when mutated genes give rise to misshapen proteins. In many of these cases, the misfolded protein is still capable of performing its function, but is incapable of reaching the place in the body where it is supposed to perform its function. Instead, it is retained by the quality control system, the cell’s endoplasmic reticulum (ER). Here the mutant proteins either accumulate, to the detriment of the cell, or are dismantled by cell mechanisms.

However, recent research indicates that there are a number of low molecular weight compounds that can either inhibit the accumulation of mutant proteins in the cell or enable them to escape the cell’s quality control system, travel to that location in the cell where they must be to perform their function, and thus allow the mutant proteins to do their work. Some of these compounds can perform both these functions.

These compounds fall into one of two categories :

  1. chemical chaperones, or
  2. pharmacological chaperones.

The former category is non-selective in its effect. That is, the chemical chaperone assists the folding of many different proteins in the cell without distinguishing among the proteins for the disease related protein. This could lead to inappropriate changes in the levels of many proteins, to the detriment of the cell. However, pharmacological chaperones interact specifically with the disease related protein and do not interact with other proteins in the cell.

Researchers propose that pharmacological chaperones work by penetrating the cell and binding with the target proteins in an early stage of their synthesis. Since the target protein is not yet mature, the chaperone is able to influence the folding of the protein so that it will be close enough to normal shape that it will not be retained by the cell’s quality control system and can travel to its work site in the cell and perform its function.

For example, mutations of the vasopressin 2 receptor (V2R) gene result in mutant V2R proteins, and this leads to the disorder known as nephrogenic diabetes insipidus (NDI). There are over 150 V2R mutations linked to NDI. Researchers tested two pharmacological chaperones on 12 such mutations and found they restored function to eight of them by helping the mutant V2Rs escape the ER.

Pharmacological chaperones offer promise for people with conformational disease. Some of them are capable of rescuing the maturation and function of many distinct forms of the same proteins, as in the case of the pharmacological chaperones used in the NDI experiments where the chaperones rescued eight of twelve different V2R mutations. Testing in laboratory cell cultures and animals indicate that, in principle, pharmacological chaperones work. Clinical studies with some of these chaperones have already started.