We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases.
- Authors
Mena ‐ Barragán, Teresa; Narita, Aya; Matias, Dino; Tiscornia, Gustavo; Nanba, Eiji; Ohno, Kousaku; Suzuki, Yoshiyuki; Higaki, Katsumi; Garcia Fernández, José Manuel; Ortiz Mellet, Carmen
- 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.
- Subjects
GLYCOSIDASE inhibitors; ENDOPLASMIC reticulum; LYSOSOMAL storage diseases; MOLECULAR chaperones; GAUCHER'S disease
- Publication
Angewandte Chemie, 2015, Vol 127, Issue 40, p11862
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201505147