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Title: Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Abstract

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe diseasemore » and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.« less

Authors:
 [1];  [2];  [1];  [2];  [2];  [1];  [3];  [2];  [1]
  1. Univ. of Cambridge, Cambridge (United Kingdom)
  2. Aarhus Univ., Aarhus (Denmark)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1214555
Grant/Contract Number:  
AC02-05CH11231; 082961/Z/07/Z; 100140; UF100371
Resource Type:
Accepted Manuscript
Journal Name:
Chemical Science
Additional Journal Information:
Journal Volume: 6; Journal Issue: 5; Journal ID: ISSN 2041-6520
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Hill, Chris H., Viuff, Agnete H., Spratley, Samantha J., Salamone, Stéphane, Christensen, Stig H., Read, Randy J., Moriarty, Nigel W., Jensen, Henrik H., and Deane, Janet E. Azasugar inhibitors as pharmacological chaperones for Krabbe disease. United States: N. p., 2015. Web. doi:10.1039/C5SC00754B.
Hill, Chris H., Viuff, Agnete H., Spratley, Samantha J., Salamone, Stéphane, Christensen, Stig H., Read, Randy J., Moriarty, Nigel W., Jensen, Henrik H., & Deane, Janet E. Azasugar inhibitors as pharmacological chaperones for Krabbe disease. United States. https://doi.org/10.1039/C5SC00754B
Hill, Chris H., Viuff, Agnete H., Spratley, Samantha J., Salamone, Stéphane, Christensen, Stig H., Read, Randy J., Moriarty, Nigel W., Jensen, Henrik H., and Deane, Janet E. Mon . "Azasugar inhibitors as pharmacological chaperones for Krabbe disease". United States. https://doi.org/10.1039/C5SC00754B. https://www.osti.gov/servlets/purl/1214555.
@article{osti_1214555,
title = {Azasugar inhibitors as pharmacological chaperones for Krabbe disease},
author = {Hill, Chris H. and Viuff, Agnete H. and Spratley, Samantha J. and Salamone, Stéphane and Christensen, Stig H. and Read, Randy J. and Moriarty, Nigel W. and Jensen, Henrik H. and Deane, Janet E.},
abstractNote = {Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.},
doi = {10.1039/C5SC00754B},
journal = {Chemical Science},
number = 5,
volume = 6,
place = {United States},
year = {Mon Mar 23 00:00:00 EDT 2015},
month = {Mon Mar 23 00:00:00 EDT 2015}
}

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