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  • Review Article
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Targeting glycosylation as a therapeutic approach

Nature Reviews Drug Discovery volume 1, pages 65–75 (2002)Cite this article

Key Points

  • Protein and lipid glycosylation are vital to fundamental cellular processes. For therapeutic strategies that target glycosylation, modulation rather than ablation of the enzymes involved is likely to be a necessity.

  • Imino sugars are monosaccharide mimics that have a nitrogen atom in place of the ring oxygen. Members of the imino-sugar family can inhibit several glycosylation enzymes, including ER α-glucosidases I and II, which are involved in processing glycoproteins, and the ceramide-specific glucosyltransferase, which is involved in glucosphingholipid (GSL) synthesis.

  • Inhibiting ER α-glucosidases can affect the folding of proteins that depend on an interaction with the chaperones calnexin and calreticulin. As the folding of some viral envelope proteins depends on this interaction, targeting ER α-glucosidases at a low level could be a potential strategy for treating viral infections, without compromising the host cell.

  • The imino sugar N-nonyl-deoxynojirimycin (N-nonyl-DNJ) has antiviral activity in an animal model of hepatitis B virus, and in bovine viral diarrhoea virus, an in vitro surrogate model of hepatitis C. Studies with the N-nonyl galactose analogue hint at an additional antiviral mechanism associated with the alkyl side chain.

  • In GSL storage diseases such as Tay–Sachs, Sandhoff and Gaucher disease, GSL species are stored in the lysosome owing to defects in enzymes in the GSL degradation pathway. Partially inhibiting GSL synthesis to redress the balance between synthesis and breakdown could compensate for these defects if some residual enzyme activity remains.

  • N-butyl-DNJ inhibits the first committed step of GSL biosynthesis, and improves disease pathology in mouse models of Tay–Sachs disease and Sandhoff disease. Data from a clinical trial of N-butyl-DNJ in patients with type I Gaucher disease indicate that GSL depletion improves all key clinical features of the disease, and these data have been submitted to regulatory authorities in Europe and the United States for approval.

Abstract

Increased understanding of the role of protein- and lipid-linked carbohydrates in a wide range of biological processes has led to interest in drugs that target the enzymes involved in glycosylation. But given the importance of carbohydrates in fundamental cellular processes such as protein folding, therapeutic strategies that modulate, rather than ablate, the activity of enzymes involved in glycosylation are likely to be a necessity. Two such approaches that use imino sugars to affect glycosylation enzymes now show considerable promise in the treatment of viral infections, such as hepatitis B, and glucosphingolipid storage disorders, such as Gaucher disease.

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Figure 1: Biosynthesis of glycoproteins that possess N-linked glycans.
Figure 2: Biosynthesis of glucosphingolipids.
Figure 3: The role of glycosylation in protein folding.
Figure 4: The glucosphingolipid cycle and glucosphingolipid storage diseases.

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Acknowledgements

F.M.P. is a Lister Institute Research Fellow. N.Z. is a Dorothy Hodgkin Royal Society Research Fellow.

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Authors and Affiliations

  1. Department of Biochemistry, Glycobiology Institute, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK

    Raymond A. Dwek, Terry D. Butters, Frances M. Platt & Nicole Zitzmann

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  1. Raymond A. Dwek
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Correspondence to Raymond A. Dwek.

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DATABASES

LocusLink

calnexin

calreticulin

CD4

ceramide galactosyltransferase

CerGlcT

chitotriosidase

ER α-glucosidase I

ER α-glucosidase II

glucocerebrosidase

HEXA

Hexa

HEXB

Hexb

β-hexosaminidase

α-mannosidase I

α-mannosidase II

NPC1

Npc1

NPC2

OMIM

Fabry disease

Gaucher type 1

Gaucher type 2

Gaucher type 3

GM2 gangliosidosis

non-insulin-dependent diabetes

NPC disease

Sandhoff disease

Tay–Sachs disease

Medscape DrugInfo

Miglitol

FURTHER INFORMATION

Encyclopedia of Life Sciences

Glycosylation and disease

Glossary

GLYCAN

A polymer consisting of monosaccharides linked together by glycosidic bonds.

ENDOPLASMIC RETICULUM

Membrane-bounded compartment in the cytoplasm of eukaryotic cells, in which lipids, membrane-bound and secreted proteins are synthesized.

GOLGI APPARATUS

Membrane-bounded organelle in eukaryotic cells, in which lipids and proteins made in the endoplasmic reticulum are modified and sorted.

GLYCOSYLTRANSFERASE

Glycosyltransferases produce glycosidic bonds by transferring a glycosyl group — any group formed by detaching the glycosidic hydroxyl group from the cyclic form of a monosaccharide, oligosaccharide or derivatives.

GLYCOSIDASE

An enzyme that hydrolyses glycosidic bonds.

LYSOSOME

Membrane-bounded organelle in eukaryotic cells responsible for controlled intracellular digestion of macromolecules. Lysosomes contain a wide range of hydrolytic enzymes, including glycosidases.

CHARGE-TRANSITION-STATE ANALOGUES

A structural mimic of the transition state between reactant(s) and product(s) for a given reaction. Transition-state analogues make good inhibitors because they are bound to the enzyme more tightly than the substrates.

ENVELOPE

A lipoprotein-bilayer outer membrane of many viruses. Envelope proteins are often heavily glycosylated.

SYNCYTIUM

A mass of cytoplasm containing several separate nuclei enclosed in a continuous membrane resulting from the fusion of individual cells.

V1/V2 LOOP

The gp120 protein has eleven defined loop segments, five of which are termed variable (designated V1–V5). The tip of one of the six non-variable loops forms a β-hairpin that hydrogen bonds with two parallel strands from the V1/V2 loop to form a β-sheet that effectively connects the inner and outer domains.

VIRAEMIA

The presence of viruses in the blood.

VIRION

A mature infectious virus particle.

PLAQUE-REDUCTION ASSAY

Virus-induced cell death causes a plaque in a cell monolayer. Plaques can be counted to indicate how much virus is present.

MULTIPLICITY OF INFECTION

(MOI). The (average) number of virus particles that infect each cell in an experiment.

MACROPHAGE

A type of white blood cell that is specialized for the uptake of material by phagocytosis.

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Dwek, R., Butters, T., Platt, F. et al. Targeting glycosylation as a therapeutic approach. Nat Rev Drug Discov 1, 65–75 (2002). https://doi.org/10.1038/nrd708

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