pH‐Responsive Pharmacological Chaperones for Rescuing Mutant Glycosidases |
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| Authors: | Dr Teresa Mena‐Barragán Aya Narita Dino Matias Dr Gustavo Tiscornia Dr Eiji Nanba Dr Kousaku Ohno Dr Yoshiyuki Suzuki Dr Katsumi Higaki Prof José Manuel Garcia Fernández Prof Carmen Ortiz Mellet |
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| Institution: | 1. Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla c/Profesor García González 1, 41011 Sevilla (Spain);2. Division of Child Neurology, Tottori University Faculty of Medicine, Yonago 683‐8504 (Japan);3. Center for Biomedical Research, Depertamento de Ciencias, Biomedicas y Medicina/Programa de Medicina Regenerativa, Universidad do Algarve (Portugal);4. Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi‐cho, Yonago 683‐8503 (Japan);5. Sanin Rosai Hospital, Yonago 683‐8605 (Japan);6. Tokyo Metropolitan Institute of Medical Science, Tokyo 204‐8588 (Japan);7. Instituto de Investigaciones Químicas (IIQ), CSIC‐Universidad de Sevilla, Américo Vespucio 49, 41092 Sevilla (Spain) |
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| 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. |
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| Keywords: | chaperones glycosidases inhibitors pH sensitivity protein folding |
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