Proposed Mechanism of Action

The following animation shows the proposed mechanism of action for pharmacological chaperones in Lysosomal Storage Disorders:

 

Proposed Mechanism of Action for Pharmacological Chaperones in Lysosomal Storage Disorders

Pharmacological chaperone technology involves the use of small molecules that selectively bind to and stabilize proteins in cells, leading to improved protein folding and trafficking, and increased activity. In lysosomal storage disorders, the target protein is an enzyme that works in the lysosome to break down substrate.  Due to genetic mutations, lysosomal enzymes may be misfolded and unstable, which may hamper the protein’s ability to be trafficked through the cell.

In lysosomal storage disorders, the binding of the pharmacological chaperone to the active site of the misfolded protein in the endoplasmic reticulum (ER) of the cell helps the protein fold into its correct three-dimensional shape. Stabilization of the protein allows the protein-chaperone complex to pass through the quality control system of the ER. The protein-chaperone complex is then properly trafficked from the ER, through the Golgi apparatus, to the lysosome, which is the protein’s final destination. Once in the lysosome, the pharmacological chaperone is displaced from the active site of the protein.  This allows the protein, which is biologically active, to break down the natural substrate in the lysosome.

Beyond lysosomal storage disorders, pharmacological chaperones have potential clinical application in a broad range of genetic diseases, including neurodegenerative disorders and other metabolic diseases.