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Título

Highly pH-Responsive Pharmacological Chaperones for Mutant Glycosidase Enhancement

AutorMena-Barragán, Teresa; Narita, Aya; Matias, Dino; Tiscornia, Gustavo; Nanba, Eiji; Ohno, Kousaku; Suzuki, Yoshiyuki; Higaki, Katsumi; García-Fernández, José Manuel; Ortiz-Mellet, Carmen
Palabras claveChaperones
Glycosidases
pH sensitivity
Inhibitors
Protein folding
Fecha de publicación2015
EditorWiley-VCH
CitaciónAngewandte Chemie - International Edition, 54)40): 11696-11700 (2015)
ResumenA 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
Versión del editorhttp://dx.doi.org/10.1002/anie.201505147
URIhttp://hdl.handle.net/10261/123024
DOI10.1002/anie.201505147
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