Co-workers: Nicole Zitzmann, Terry D. Butters, Paul Wentworth, Mark R. Wormald, Dr Chris Scanlan
Professor Raymond A Dwek, FRS is Director of the Glycobiology Institute where there are five main groups:
- Dr Nicole Zitzmann - Antiviral Iminosugars and Oxford Glycoproteomics
- Dr Terry D. Butters - Chemistry and biology of imino sugar inhibitors
- Prof Paul Wentworth - Chemical biology and application to disease
- Dr Mark R. Wormald - Structural glycobiology
- Dr Chris Scanlan - Carbohydrate-based vaccine design for HIV/AIDS
Research in glycobiology has made major contributions to understanding concepts in protein folding, immunology and virology, laying the foundations for applying glycobiology to the development of novel strategies for antiviral therapeutics and vaccines.
Viruses are a major public health concern associated with considerable morbidity and mortality worldwide. Over two billion people, of which 350 million are chronically infected, have been or are infected with Hepatitis B virus (HBV); 200 million people are infected with Hepatitis C virus (HCV), and over 40 million are infected with HIV. Each of these viruses is dependent on their properly folded coat glycoproteins for their infectivity.
Iminosugar drugs that disrupt the folding of these glycoproteins are being investigated as antiviral therapeutics in the Oxford Antiviral Drug Discovery Unit. One such compound, the glucose analogue N-butyl-deoxynojirimycin (NB-DNJ), was pioneered by the Oxford Glycobiology Institute and has world-wide approval for use in treatment of glycolipid storage disorders. But NB-DNJ is also effective against HCV, HBV, and HIV and methods to improve the targeted delivery of this drug are in development. These include ER-targeting liopsomes. Building on this research, other mechanisms of inhibiting the morphogenesis (the assembly and secretion of infectious virus) of HCV are being investigated.
Knowledge of glycobiology is also being exploited in the design of a novel, antibody-based HIV vaccine. Methods to break "tolerance" to the sugars covering the virus are being explored. The basis for this is a rare neutralising antibody, obtained from a patient, that recognises clusters of sugars on the "immunologically silent" face of HIV.
- Review - Exploiting the defensive sugars of HIV-1 for drug and vaccine design. C.N. Scanlan, J. Offer, N. Zitzmann and R.A. Dwek (2007) Nature 446, 1038-1045
- The Impact of Glycosylation on the Biological Functions of Human Immunoglobulins. Arnold, J.N., Wormald, M.R., Sim, R.B., Rudd, P.M. and Dwek, R.A. (2007) Ann. Rev. Immunol., 25, 21-50
- Targeting Glycosylation as a Therapeutic Approach. Dwek, R.A., Butters, T.D., Platt, F.M. and Zitzmann, N. (2001), Nature Reviews, 65-75
- N-butyldeoxynojirimycin is a broadly effective anti-HIV therapy significantly enhanced by targeted liposome delivery. S. Pollock, R.A. Dwek, D.R. Burton, and N. Zitzmann (2008) AIDS, 22, 1961-1969
- Glycobiology at Oxford a Personal View. Dwek, R.A. (2006) The Biochemist, 28, 4-7
Figure 1: Structure function relationships in N-bdeoxynojirimicin. Left – structural elements important for glucosidase inhibition (with potential anti-viral activity); right – structural elements important for glucosyl-ceramide transferase inhibition (treatment of glycolipid storage disorders).
Figure 2: Zavesca, the first oral therapy for Type 1 Gaucher disease, has been in patients for over seven years.
Figure 3: Model of the HCV p7 ion channel (Partargias, et al., J. Med. Chem., 2006, 49, 648-655) Treatment with N-nonyl-deoxynojirimycin inhibits channel activity (right)
Figure 4: Liposomes are lipid-based nanoparticles that can be used for delivery of small molecules inside the cell. A human DAPI- (blue nuclei) and fluorescein- (green ER membranes) stained hepatoma cell line was incubated with rhodamine-labeled pH-sensitive (top panel) or ER targeting (bottom panel) liposomes (red) and analysed by confocal fluorescent microscopy, showing co-localisation of liposomal lipids and the ER membrane in bottom panel only.