Terry Butters
Chemistry and biology of imino sugar inhibitors
Co-workers: Dr Dominic Alonzi, Gabriele Reinkensmeier, Elizabeth Crabtree
Katherine Patzel, Marvin Lee, Nikolay Kukushkin, Dr Sarah Allman, Dr Andrew Stachulski, Aime Lopez Aguilar, Andreas Glawar
The use of small molecule inhibitors to enzymes involved in glycoconjugate metabolism is being explored in a number of therapeutic applications. These projects aim to understand the biochemical mechanism for action of inhibitors in a cellular environment.
When misfolded glycoproteins are removed from the ER and targeted for proteolytic degradation, the analysis of free N-linked oligosaccharides that are generated offer a simple marker for ER-regulated protein misfolding. The characterisation of these free oligosaccharides reveals pathways for clearance and can be used to quantitatively measure the effects of inhibitors on ER-resident glycoprotein processing -glucosidases. The design and synthesis of novel -glucosidase inhibitors that gain entry to the ER and disrupt protein-folding pathways at submicromolar concentrations are being evaluated for inhibition of viral (HIV, hepatitis) infectivity.
In many human GLSD, mutations in the gene result in incorrectly folded glycosidase protein that fails to traffic to the lysosome leading to decreased enzyme activity and substrate accumulation. Specific imino sugar inhibitors improve protein folding and enhance catalytic activity. Strategies that aim to understand this mechanism and promote the design and synthesis of selective inhibitors offer a novel and disease-specific treatment for GLSD, such as Gaucher and Fabry disease, and the Gangliosidoses.
Publications
- Design and synthesis of iminosugar-based inhibitors of glucosylceramide synthase: the search for new therapeutic agents against Gaucher disease.Boucheron, C., Desvergnes, V., Compain, P., Martin, O.R., Lavi, A., Mackeen, M., Wormald, M.R., Dwek, R.A. and Butters, T.D. (2005) Tetrahedron Asymmetry, 16, 1747-1756
- Imino sugar inhibitors for treating the lysosomal glycosphingolipidoses Butters, T.D. (2007) in Iminosugars: from synthesis to therapeutic applications (Compain, O. and Martin, P. Eds) J Wiley & Son Ltd., Chichester, UK
- Glucosylated Free Oligosaccharides are Biomarkers of Endoplasmic Reticulum -Glucosidase Inhibition Alonzi, D.S., Neville, D.C.A., Lachmann, R.H., Dwek, R.A. and Butters, T.D. (2008) Biochem J 409, 571-580
- Design, synthesis and biological evaluation of enantiomeric beta-N-acetylhexosaminidase inhibitors LABNAc and DABNAc as potential agents against Tay-Sachs and Sandhoff disease Rountree, J. S. S., Butters, T. D., Wormald, M. R., Boomkamp, S. D., Dwek, R. A., Asano, N., Ikeda, K., Evinson, E. L., Nash, R. J. and Fleet, G. W. J. (2009) ChemMedChem (in press)
- Development of a single column method for the separation of lipid- and protein-derived oligosaccharides Neville, D. C. A., Dwek, R. A. and Butters, T. D. (2009) J Proteome Res 8
More Publications...
Research Images
Figure 1: In silico structural model of ceramide-specific glycosyltransferase docked with ceramide
Figure 2: Solution structure of the imino sugar
NB-DNJ (blue) overlaid with ceramide (green)
to show structural similarity
Figure 3: Human macrophage chemically induced to store
glucosylceramide in the lysosome - the Gaucher phenotype
Contact: terry.butters@bioch.ox.ac.uk
Graduate Student and Postdoctoral Positions: No positions currently available
Website: http://www2.bioch.ox.ac.uk/~terryb