pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

A general approach is reported for the design of small‐molecule competitive inhibitors of lysosomal glycosidases programmed to 1) promote correct folding of mutant enzymes at the endoplasmic reticulum, 2) facilitate trafficking, and 3) undergo dissociation and self‐inactivation at the lysosome. The strategy is based on the incorporation of an orthoester segment into iminosugar conjugates to switch the nature of the aglycone moiety from hydrophobic to hydrophilic in the pH 7 to pH 5 window, which has a dramatic effect on the enzyme binding affinity. As a proof of concept, new highly pH‐responsive glycomimetics targeting human glucocerebrosidase or α‐galactosidase with strong potential as pharmacological chaperones for Gaucher or Fabry disease, respectively, were developed. pH‐Responsive chaperones for rescuing mutant lysosomal glycosidases were developed by incorporating an acid‐labile orthoester into sp2‐iminosugar conjugates. In the endoplasmic reticulum (ER; pH 7), the chaperone binds to the mutant enzyme and promotes correct folding and trafficking. In the lysosome (pH 5), fast hydrolysis of the orthoester leads to inactivation of the chaperone.