Discovery, SAR, and Biological Evaluation of Non-inhibitory Chaperones of Glucocerebrosidase

Gaucher disease is a rare genetic lysosomal storage disease characterized by a loss of function in the glucocerebrosidase (GCase) enzyme, which is responsible for hydrolyzing glucocerebroside (GC) in the lysosome. When cells die, macrophages use GCase to break down GC, a major constituent of cell walls. With deficient functional GCase, GC accumulates within the lysosome, giving rise to the appearance of bloated Gaucher cells; this is a hallmark of the disease. Certain mutated GCase proteins, after production in the endoplasmic reticulum (ER), do not fold properly and are degraded via the proteasome pathway instead of being transported to the lysosome. One therapeutic strategy is to develop small molecule chaperones, which upon binding to GCase ensure proper folding and subsequent transport of the mutant protein to the lysosome, where it can resume activity. The main challenge in the development of molecular chaperones for Gaucher disease is that all of the previously described chaperones are inhibitors of the enzyme. This complicates their clinical development, because it is difficult to generate an appropriate in vivo exposure at which a compound exhibits chaperone activity, but does not inhibit the enzyme’s function. Using high throughput screening, we have identified two chemical series that do not inhibit the enzyme’s action, but can still facilitate its translocation to the lysosome as measured by immunostaining of glucocerebrosidase in patient fibroblasts. These chemical series are exemplified by ML198 and ML266. These compounds serve as starting points to develop a novel approach towards small molecule treatment for patients suffering from Gaucher disease.

 

Comments：

Gaucher disease is a rare genetic disorder caused by a deficiency in the glucocerebrosidase (GCase) enzyme, which leads to an accumulation of glucocerebroside (GC) in lysosomes. This accumulation causes bloated Gaucher cells, a hallmark of the disease. A possible therapeutic strategy involves using small molecule chaperones to help mutant GCase fold correctly and transport to the lysosome, where it can function. However, previous chaperones have also inhibited the enzyme's activity, making it challenging to develop a treatment.

Using high-throughput screening, two chemical series, ML198 and ML266, have been identified that do not inhibit the enzyme's action but can facilitate its translocation to the lysosome. These compounds can serve as starting points to develop a novel approach to treating Gaucher disease with small molecules that do not inhibit enzyme activity. Further research will be needed to determine their effectiveness and safety for clinical use.

Related Products

Cat.No.	Product Name	Information
S3470	ML198	ML198 is a novel activator of glucocerebrosidase (GCase) with an IC50 of 0.4 μM and does not inhibit the enzyme's action, but can facilitate its translocation to the lysosome.

Related Targets

glucocerebrosidase