A contradictory treatment for lysosomal storage disorders: inhibitors enhance mutant enzyme activity

Small molecules are proposed as potential drugs for the treatment of lysosomal storage disorders (LSDs) such as Fabry disease and Gaucher disease, which are caused by deficiencies in lysosomal enzymes. Certain mutations in the disease-causing enzymes result in the synthesis of improperly folded proteins that are retarded in the endoplasmic reticulum (ER) and degraded by ER-associated degradation. However, these proteins might be enzymatically active if they could be transported properly to lysosomes. At sub-inhibitory concentrations, potent competitive inhibitors of the mutant enzymes can act as active-site-specific chaperones that either induce or stabilize the proper conformation of the mutant enzyme. This promotes normal trafficking through the secretory pathway of the ER and, ultimately, increases enzyme activity in lysosomes. This therapeutic strategy, of using functional chemicals as pharmacological chaperones, could be applied broadly to other LSDs and genetic metabolic diseases that are caused by misfolding of mutant proteins.