Bruno Gasnier

Université Paris Cité, SPPIN, CNRS

Prototyping small molecules that rescue the trafficking defect for common Salla mutation

The most common molecular alteration observed in Salla disease is the so called R39C mutation where the amino acid arginine is replaced with cysteine.  This apparently small change results in an important region of the SLC17A5 transporter being more flexible.  This flexibility impacts protein function in two critical ways: (i) trafficking of the protein to the intended location in the cell i.e. the lysosome and (ii) transport of sialic acid through the transporter.  Salla patients with two copies of the R39C mutation likely have less than 10% transport capacity versus normal individuals due to a combination of these two factors.

In the past few years, exciting progress has been made in the development of therapeutics that correct genetic defects associated with ion channels or other transport proteins.  One of the best examples is the case of cystic fibrosis where small molecule drugs, called ‘molecular chaperones’, can correct the trafficking and potentiate the function of the CFTR ion channel.  The recent approval of ivacaftor and lumacaftor have transformed the lives of patients with cystic fibrosis because these molecules treat the underlying cause of the disease.

Dr Gasnier and his team at CNRS in Paris have been studying SLC17A5 and lysosomal transport for many years.  In work recently published in the Journal of Medicinal Chemistry, Gasnier and colleagues reported for the first time molecular chaperones that can correct the trafficking of the R39C transporter.  This suggests that the R&D strategy that was so successful with cystic fibrosis could be applied to Salla disease.  

One of the most promising molecules highlighted in the paper is labeled Compound 45 shown bound to the protein below.

Specialized tools developed in Dr Gasnier’s laboratory allow the trafficking of the transporter to be measured directed.  In the figure below, Compound 45 largely corrects trafficking in the R39C mutant.

A diagram of a molecule.

Using advanced molecular modelling techniques, Dr Gasnier’s team is now further refining these molecules as the basis for a potential future clinical study in patients. The promise of this work is of great interest to the Salla community and Dr Gasnier’s team recently received an award from the STAR Foundation to further progress its research.

As molecules like Compound 45 are further optimized, they could form the basis of disease modifying therapies for patients with Salla Disease, where about 75% of patients harbor the R39C mutation.