pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

Abstract

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.

Conducting polymer nanoparticles for a voltage-controlled release of pharmacological chaperones

“…The hallmark of PCs is their ability to bind and stabilize their target proteins. [1][2][3][4][5][6] Although the use of PCs is considered a potential therapeutic strategy for the treatment of conformational diseases (i.e. those caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation), the administration of too high doses by oral or intravenous routes can be sometimes counterproductive due to the inhibition of the target protein.…”