Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

  • Chris H. Hill, Univ Cambridge, University of Cambridge, Cambridge Inst Med Res, Dept Haematol
  • ,
  • Agnete Viuff, Danmark
  • Samantha J. Spratley, Univ Cambridge, University of Cambridge, Cambridge Inst Med Res, Dept Haematol
  • ,
  • Stephane Salamone, Aarhus Univ, Aarhus University, Dept Chem, Danmark
  • Stig H. Christensen, Aarhus Univ, Aarhus University, Dept Chem, Danmark
  • Randy J. Read, Univ Cambridge, University of Cambridge, Cambridge Inst Med Res, Dept Haematol
  • ,
  • Nigel W. Moriarty, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Ukendt
  • Henrik Helligsø Jensen
  • Janet E. Deane, Univ Cambridge, University of Cambridge, Cambridge Inst Med Res, Dept Haematol

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme beta-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.

OriginalsprogEngelsk
TidsskriftChemical Science
Vol/bind6
Nummer5
Sider (fra-til)3075-3086
Antal sider12
ISSN2041-6520
DOI
StatusUdgivet - 2015

Se relationer på Aarhus Universitet Citationsformater

ID: 86906137