Dr Terry D. Butters, MPhil, PhD - contact details
Senior Research Fellow of the Glycobiology Institute

Dr Frances M. Platt, BSc, PhD - contact details
Lister Institute Research Fellow

Protein and lipid-linked oligosaccharides are a large component of the eukaryotic cell surface where they play important roles in cell-cell and cell-pathogen interactions and adhesion. Alterations in both the synthesis or catabolism of these oligosaccharides have serious and life threatening consequences, such as tumour metastasis, carbohydrate deficiency syndromes and lysosomal storage diseases.

The experimental manipulation of oligosaccharide biosynthesis by the use of enzyme specific inhibitors has proved useful in understanding the functional roles of protein-linked oligosaccharides. When the early stages of oligosaccharide maturation are blocked with a-glucosidase inhibitors, such as N-butyl-deoxynojirimycin, many glycoproteins fail to undergo chaperone-mediated protein folding, leading to an altered conformation and loss of biological activity. This discovery has lead to the exploitation of processing inhibitors as anti-viral (HIV and Hepatitis B) therapeutics (Collaborators: Professor Tim Block, Jefferson Medical College, USA).

In addition to being potent glycosidase inhibitors, certain members of the deoxynojirmycin family of sugar mimics also act as a ceramide-specific glucosyltransferase inhibitor. The glucosyltransferase is a key enzyme in the pathway for the synthesis of the lactosyl-, and globosyl-ceramide series, and gangliosides. In cells and in vivo, inhibitor treatment can prevent the synthesis of most glycosphingolipids and are therefore model systems for understanding glycolipid biology (Collaborators: Dr Tom Seyfried, Boston College, USA, Professor Tim Mitchell, Glasgow University). Study of the glucosyltransferase/inhibitor interactions enables further definition of glycolipid trafficking in the cell and dissection at the molecular level permits better inhibitor design (Collaborators: Professor Yoshio Hirabayashi, RIKEN, Tokyo, Japan, Dr George Fleet, Dyson Perrins Laboratory, University of Oxford).

The use of these novel glycolipid inhibitors allows evaluation of a ‘substrate deprivation strategy’ for the treatment of human glycosphingolipid lysosomal storage diseases. A reduction in the level of newly synthesised glycolipid allows the partially active lysosomal enzyme present in these disease states to catabolise the stored products preventing the associated pathology. Mouse knockout models for several of the human diseases are being assessed for therapeutic efficacy that will provide the basis for human trials (Collaborators: Dr Hugh Perry, Department of Pharmacology, University of Oxford, Dr Rick Proia, NIH, Bethesda, USA, Professor Bryan Winchester, ICH, London, Professor Timothy Cox, University of Cambridge).

Selected recent publications :

The a-Glucosidase Inhibitor N-Butyldeoxynojirimycin Inhibits Human Immunodeficiency Virus Entry at the Post-CD4 Binding Level.
P.B. Fischer, M. Collin, G.B. Karlsson, W. James, T.D. Butters, S.J. Davis, S. Gordon, R.A. Dwek and F.M. Platt (1995) J. Virology, 69, 5791-5797.

Evidence that N-linked glycosylation is necessary for hepatitis B virus secretion.
X. Lu, A. Mehta, R.A. Dwek, T.D. Butters and T.M. Block (1995) Virology, 213, 660-665

Inhibition of N-glycan processing in B16 Melanoma cells results in inactivation of tyrosinase but does not prevent its transport to the melanosome.
S.M. Petrescu, A.J. Petrescu, H.N. Titu, R.A. Dwek and F.M. Platt (1997) J. Biol. Chem., 272, 15796-15803.

Inhibitors of Glycosphingolipid Biosynthesis.
F.M. Platt and T.D. Butters (1995) Trends in Glycoscience and Glycotechnology, 7, 495-511.

Prevention of Lysosomal Storage in Tay-Sachs Mice Treated with N-butyldeoxynojirmycin.
F.M. Platt, G.R. Neises, G. Reinkensmeier, M.J. Townsend, V.H. Perry, R.L. Proia, B. Winchester, R.A. Dwek and T.D. Butters (1997) Science, 276, 428-431.