pH-Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases

• Published in: Angewandte Chemie 2015-09, Vol.127 (40), p.11862-11866
• Main 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
• Format: Article
• Language: eng ; ger
• Subjects: Chaperone; Chemistry; Conjugates; Endoplasmic reticulum; Enzymes; Glycosidases; Glykosidasen; Human; Inhibitoren; Lysosomes; pH-Responsivität; Proteinfaltung; Segments; Strategy; Switches
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201505147

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 Chaperone zur Rettung lysosomaler Glykosidase‐Mutanten beruhen auf einem säurelabilen Orthoester in sp2‐Iminozucker‐Konjugaten. Im endoplasmatischen Reticulum (ER; pH 7) bindet das Chaperon an die Enzymmutante und stellt die korrekte Faltung und Platzierung sicher. Im Lysosom (pH 5) desaktiviert die schnelle Orthoesterhydrolyse das Chaperon.