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Azasugar inhibitors as pharmacological chaperones for Krabbe disease

DOI: 10.1039/C5SC00754B DOI Help
PMID: 26029356 PMID Help

Authors: Chris H. Hill (University of Cambridge) , Agnete Viuff (Aarhus University) , Samantha Spratley (University of Cambridge) , Stéphane Salamone (Aarhus University) , Stig H. Christensen (Aarhus University) , Randy Read (University of Cambridge) , Nigel W. Moriarty (Lawrence Berkeley National Laboratory) , Henrik H. Jensen (Aarhus University) , Janet E. Deane (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 6 (5) , PAGES 3075 - 3086

State: Published (Approved)
Published: May 2015
Diamond Proposal Number(s): 8547

Open Access Open Access

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 b-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.

Diamond Keywords: Krabbe Disease

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/09/2015 12:53

Documents:
c5sc00754b.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)